Fight Aging!

Every cell contains a herd of hundreds of mitochondria, bacterial-like structures that contain a small circular genome, the mitochondrial DNA. Mitochondria replicate to make up their numbers, and are culled by the quality control mechanism of mitophagy when damaged. Their primary task is to conduct the energetic chemistry that packages the energy store molecule adenosine triphosphate, used to power cellular processes. Mitochondrial function declines with age for reasons that are still comparatively poorly understood; damage to mitochondrial DNA is involved, as are changes in the expression of proteins necessary for mitophagy to function correctly.

One crude way to assess the state of mitochondria in cells is to count the number of copies of mitochondrial DNA that are present, a number that changes with aging and disease. While there is plenty of evidence for this to correlate with mitochondrial dysfunction, it doesn't necessarily directly reflect the most interesting mechanisms in mitochondrial aging, which are all forms of damage to mitochondria and mitochondrial DNA, rather than outright loss of mitochondria. There is a web of damage and dysfunction, and while various different parts of it will tend to be in sync, that doesn't have to imply direct causal connections.

Thinking outside the nucleus: Mitochondrial DNA copy number in health and disease

Mitochondrial dysfunction, generally characterized as a loss of efficiency in oxidative phosphorylation, is a hallmark of aging and a variety of chronic diseases. Mitochondrial dysfunction results in inefficient cellular energy production and in increased levels of reactive oxygen species (ROS) which may damage lipids, proteins, and nucleic acids. Mitochondrial dysfunction also affects the expression of nuclear genes involved in metabolism, growth, differentiation, and apoptosis. All these changes may explain the contribution of mitochondrial dysfunction to chronic and complex human diseases.

A major limitation to the routine evaluation of mitochondrial dysfunction in clinical practice is the lack of reliable measures of mitochondrial dysfunction available for clinical use. Mitochondrial DNA copy number (mtDNA-CN) is a promising biomarker of mitochondrial dysfunction that has the potential to become widely available in clinical practice. Other measures of mitochondrial dysfunction, including cell culture-based methods are optimized in vitro, do not make use of pre-existing datasets, and cannot be scaled-up for widespread use.

An emerging body of evidence supports roles for mtDNA in the complex underpinnings of a variety of diseases, including a number of cancers and aging-related disorders. A common link in these studies include anti-inflammatory pathways. These mechanisms will be further elucidated as our ability to measure mtDNA-CN from sequencing and microarray technologies expands. As studies increase in power and functional assessment of mechanisms underlying the effect of mtDNA on mitochondrial function and gene expression improve, our understanding of variation in mtDNA-CN as cause or consequence of disease development will rapidly improve.

mtDNA-CN is an especially attractive biomarker because its measurement in blood is both non-invasive and relatively cost-friendly to obtain. The proposed utility of mtDNA-CN as a biomarker for disease has been suggested by the observation that mtDNA content can differentiate healthy controls from patients with cancer and other diseases. In addition, mtDNA-CN has been shown to be relevant for risk reclassification for cardiovascular disease. Currently, these applications are limited by several analytical factors affecting the accurate and reproducible quantification of mtDNA-CN. The recent confirmation that human mtDNA is methylated adds yet another level of complexity to the crosstalk between the nucleus and mitochondrion and its control. We close by suggesting that improved detection techniques for mtDNA-CN as well as greater understanding of the mechanisms underlying individual, cell-type, and tissue-specific variation in mtDNA-CN are essential to determining the direct pathological, therapeutic and/or clinical relevance of this relatively cost-effective and easily measured biomarker.

Whales are among the longest lived mammals, and thus of interest to researchers investigating the comparative biology of aging. There is the hope that examining the biochemistry of mammals with exceptional longevity may point the way to therapies that can slow human aging. The odds of this being the case are unknown at present: too little progress has been made to assess whether or not the differences between species will be useful as a basis for the near term development of treatments to be applied to older adults. A more realistic expectation is that these differences in biochemistry could help to prioritize work on rejuvenation therapies by pointing out which portions of cellular metabolism are more important to aging.

One important question in aging research is how differences in genomics and transcriptomics determine the maximum lifespan in various species. Despite recent progress, much is still unclear on the topic, partly due to the lack of samples in non-model organisms and due to challenges in direct comparisons of transcriptomes from different species. The novel ranking-based method that we employ here is used to analyze gene expression in the gray whale and compare its de novo assembled transcriptome with that of other long- and short-lived mammals.

Gray whales are among the top 1% longest-lived mammals. Despite the extreme environment, or maybe due to a remarkable adaptation to its habitat (intermittent hypoxia, Arctic water, and high pressure), gray whales reach at least the age of 77 years. In this work, we show that long-lived mammals share common gene expression patterns between themselves, including high expression of DNA maintenance and repair, ubiquitination, apoptosis, and immune responses. Additionally, the level of expression for gray whale orthologs of pro- and anti-longevity genes found in model organisms is in support of their alleged role and direction in lifespan determination.

Remarkably, among highly expressed pro-longevity genes many are stress-related, reflecting an adaptation to extreme environmental conditions. The conducted analysis suggests that the gray whale potentially possesses high resistance to cancer and stress, at least in part ensuring its longevity.

Link: https://doi.org/10.1111/acel.13158

A research team has recently investigated a role for BPIFB4 in human longevity. They have identified a variant of this gene that appears more often in a population of long-lived individuals than in other people. They have also investigated how this gene might influence aging; the present view is that it acts to make a larger fraction of monocytes and macrophages adopt the M2 anti-inflammatory phenotype than would otherwise be the case. Chronic inflammation is highly influential in the progression of aging and age-related disease, and thus we should probably expect long-lived individuals to exhibit better control of inflammation to at least some degree.

In industrialized countries, lifespan averages 78 for males and 83 for females, but some exceptional individuals delay aging and live much longer than the rest of the population. Long Living Individuals (LLIs) represent a model of positive biology. We posit that the peripheral blood of LLIs may hold valuable biomarkers associated with an enduring performance of the immune system. Circulating factors unique to LLIs may also be directly involved in maintaining a proper balance between M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophage phenotypes.

The bactericidal/permeability-increasing fold-containing-family-B-member-4 (BPIFB4) is one of the most abundant proteins in respiratory secretions. BPIFB4 expression is highly responsive to airborne pathogens and participates in host protection. Of note, circulating BPIFB4 levels are constitutively increased in healthy LLIs as compared to frail ones and young controls. Moreover, carriers of the longevity-associated variant (LAV) have extremely prolonged life expectancy and show higher circulating BPIFB4 levels as compared with carrier of the wild-type haplotype.

We hypothesize that BPIFB4 may influence monocytes pool and macrophages skewing, shifting the balance toward an anti-inflammatory phenotype. We profiled circulating monocytes in 52 LLIs (median-age 97) and 52 healthy volunteers (median-age 55). If the frequency of total monocyte did not change, the intermediate CD14++CD16+ monocytes counts were lower in LLIs compared to control adults. Conversely, non-classical CD14+CD16++ monocyte counts, which are M2 macrophage precursors with an immunomodulatory function, were found significantly associated with the LLIs' state.

In a differentiation assay, supplementation of the LLIs' plasma enhanced the capacity of monocytes, either from LLIs or controls, to acquire a paracrine M2 phenotype. A neutralizing antibody against BPIFB4 blunted the M2 skewing effect of the LLIs' plasma. This data indicates that LLIs carry a peculiar anti-inflammatory myeloid profile, which is associated with and possibly sustained by high circulating levels of BPIFB4. Supplementation of recombinant BPIFB4 may represent a novel means to attenuate inflammation-related conditions typical of unhealthy aging.

Link: https://doi.org/10.3389/fimmu.2020.01034

In today's research materials, scientists investigating the aging of the brain report on their use short-lived killifish. The researchers show that a decline in proteasomal function precedes the destabilization of protein complexes and the formation of harmful protein aggregates, a feature of neurodegenerative conditions. The proteasome is a complex piece of protein machinery, an assembly of numerous distinct proteins into a functional whole. It is responsible for breaking down unwanted and damaged proteins, recycling their component parts to be reused in the synthesis of other proteins.

Increases in proteasomal activity have been shown to improve health and longevity in short-lived species. This has largely been achieved by providing increased amounts of rate-limiting protein components of a proteasome, thereby increasing the number of functional proteasomes present in cells. A lack of proteasomal activity should be damaging to cells in a number of ways, both by allowing broken proteins and other molecular waste to persist, but also by reducing the supply of recycled raw materials for protein synthesis. Indeed, it is well understood that proteasomal activity declines with age, and it is not surprising to see this decline implicated as a contributing cause of age-related degeneration.

Out of balance - Ability to eliminate spent proteins influences brain aging and individual life span

Researchers have used transcriptomic and proteomic methods to investigate the chain of molecular events that lead to loss of protein homeostasis during brain aging. The researchers used Nothobranchius furzeri (killifish) as a model of aging to study mechanisms triggering protein homeostasis dysfunction. They have a life span of only 3-12 months, and thus age-dependent processes are exacerbated in this species, making it easier to detect changes in the concentration of RNAs and proteins, as compared to other model organisms.

"When comparing the data for the different age groups, we found that almost half of the approximately 9000 proteins that we managed to quantify are affected by aging." These age-related changes result in abnormal regulation of proteins (subunits) that compose macromolecular protein complexes, the types of machinery responsible for all cellular activities. Protein complexes are built by different proteins that need to be assembled in specific ratios. Our cells have mechanisms to guarantee the proper building of these complexes by regulating the precise (stoichiometric) number of specific subunits. This tightly regulated process, however, is impaired in aging.

There is a progressive loss of stoichiometry of protein complexes during aging, mainly affecting the ribosome, which is one of the most important protein complexes in the cell, responsible for producing all other proteins. The researchers demonstrated that ribosomes do not get adequately formed in old brains and aggregate, potentially influencing vital functions in the cell. Aggregation of ribosomes is not exclusive to killifish but also happens in mice, suggesting it is a conserved feature of brain aging.

Proteasomes are complexes of protein molecules that digest and recycle old or defective proteins and are an essential part of the protein homeostasis network ("garbage chipper" of the cell). The authors were able to show that proteasome activity is reduced early and progressively during the course of adult life and causes loss of protein complexes stoichiometry. They induced a reduction of proteasome activity during early adult life of the killifish using a specific drug for just four days and observed a premature aging signature including disrupted ratios of several protein complexes.  

The team also compared the gene expression data of more than 150 killifish with their lifespan. The analysis showed that the individuals' lifespan could be predicted based on changes in the expression of genes encoding for proteasomal proteins: fish that showed a greater decrease in proteasome transcripts at the beginning of life lived considerably shorter than fish able to maintain or increase proteasome expression. This finding supports the hypothesis that the reduction of proteasome activity is an early driver of aging in vertebrates.

Reduced proteasome activity in the aging brain results in ribosome stoichiometry loss and aggregation

A progressive loss of protein homeostasis is characteristic of aging and a driver of neurodegeneration. To investigate this process quantitatively, we characterized proteome dynamics during brain aging in the short-lived vertebrate Nothobranchius furzeri combining transcriptomics and proteomics. We detected a progressive reduction in the correlation between protein and mRNA, mainly due to post-transcriptional mechanisms that account for over 40% of the age-regulated proteins. These changes cause a progressive loss of stoichiometry in several protein complexes, including ribosomes, which show impaired assembly/disassembly and are enriched in protein aggregates in old brains.

Mechanistically, we show that reduction of proteasome activity is an early event during brain aging and is sufficient to induce proteomic signatures of aging and loss of stoichiometry in vivo. Using longitudinal transcriptomic data, we show that the magnitude of early life decline in proteasome levels is a major risk factor for mortality. Our work defines causative events in the aging process that can be targeted to prevent loss of protein homeostasis and delay the onset of age-related neurodegeneration.

Loss of mitochondrial function is important in aging. Mitochondria are the power plants of the cell, a herd of bacteria-like organelles that contain their own mitochondrial DNA, constantly replicate by division or fuse together, and work to package the chemical energy store molecule adenosine triphosphate, used to power cellular processes. Numerous mechanisms are implicated in the age-related disruption of mitochondrial function, and many of them relate to quality control, either of individual mitochondrial proteins, or of the entire mitochondrion. For example, there is evidence for an age-related imbalance in mitochondrial fusion and fission to lead to overly large mitochondria that are resistant to the quality control mechanism of mitophagy - and thus they become worn and dysfunctional and are not replaced.

Pathophysiological stress often damages mitochondria in myocytes which are vital for the heart's contractile activity. Therefore, continuous monitoring and repair of mitochondria are needed to maintain a healthy mitochondrial population in cells. Multiple levels of mitochondrial quality control exist both at the protein and organelle level.

First, because the majority of mitochondrial proteins are encoded in the nucleus, significant monitoring of mitochondrial precursor proteins is needed during their cytosolic translation and import. The ubiquitin-proteasome system shapes the mitochondrial proteome through steady-state turnover of mitochondrial precursors to ensure an appropriate stoichiometry between nuclear and mitochondrially encoded proteins and their proper localization. Second, mitochondria contain resident chaperones and proteases to ensure quality control within the mitochondria. Third, excessive levels of misfolded proteins in the mitochondrial matrix or a mito-nuclear protein imbalance activates a conserved mitochondrial ubuqiutin-proteasome system which functions to selectively induce a transcriptional response aimed at restoring mitochondrial proteostasis.

A closer examination into these processes reveals an inextricable link between mitochondrial quality control and cytosolic proteostasis. More recently, mitochondria themselves have been found to participate in general protein quality control through the import and degradation of misfolded cytosolic proteins.

In the event that the mitochondria cannot be repaired, myocytes have the option of either eliminating damaged mitochondrial components via mitochondrial-derived vesicles, or by removing the entire organelle through mitophagy. Elimination of the entire mitochondria is likely a last resort response because it requires the cell to replace the mitochondrion.

Continued investigations into the molecular drivers of mitochondrial quality have the potential to elucidate novel interventions for general the proteostatic stress seen during myocardial ischemia, pressure overload, and protein aggregation cardiomyopathies. Collectively, these mitochondrial quality control pathways represent essential adaptive responses in cardiac myocytes, and fruitful avenues for the development of novel therapies against cardiovascular diseases. Once a better understanding of the regulators and relationships between the various quality control pathways is gained, we will hopefully be able to translate this knowledge into improved treatments for disease.

Link: https://doi.org/10.3389/fphys.2020.00515

Researchers here argue that it was a mistake to omit from the hallmarks of aging of cross-links and other forms of persistent modification to extracellular matrix molecules. Cross-links degrade the elasticity and other structural properties of tissue, something that is concerning in skin and much more serious in blood vessels, as it contributes to hypertension and cardiovascular mortality. Cross-linking has, of course, long been prominent in the SENS outline of the causes of aging and how to best reverse them. The SENS Research Foundation funded academic work that led to the launch of Revel Pharmaceuticals, a company undertaking the clinical development of cross-link breaking enzymes targeting the most common form of persistent cross-link in humans, those involving glucosepane.

Aging is undoubtedly one of the most important and yet unsolved problems of humanity. Many theories have been put forward, but none have yet been fully verified. Modern geroscience enumerates nine hallmarks that represent common denominators of aging in different organisms, with special emphasis on mammalian aging. The proposed hallmarks are genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. However, this list is missing one particularly important hallmark: stochastic non-enzymatic modification of long-lived macromolecules.

First proposed in 1942, the cross-linking theory of aging postulates that aging results from the accumulation of intra-intermolecular covalent bonds (crosslinks) between molecules with slow turnovers, such as collagen and elastin of the extracellular matrix (ECM). These crosslinks affect the physical properties of the ECM (i. e. stiffness) which may cause cell dysfunction via mechanosensing. Additionally, there also exist adducts which may cause inflammation via activation of the receptor for advanced glycation endproducts (RAGE). We also think that ECM aging might be even more important than cellular aging since cells have effective mechanisms to repair or remove damaged proteins and organelles.

These modifications are a consequence of the biochemistry and the long turnover of some macromolecules and do not require any dysregulation of molecular pathways. Additionally, these modifications give rise to virtually all hallmarks of aging and age-related pathologies, which makes it an ideal candidate for the starting point of the vicious cycle of aging. Organisms with remarkably long lifespans like bowhead whale have exceptionally low rates of advanced glycation endproducts accumulation, which gives a hope that interventions that slow down the accumulation of non-enzymatic modifications should dramatically decrease the rate of aging and thus prolong both lifespan and healthspan.

Link: https://doi.org/10.1016/j.arr.2020.101097

In today's open access research, the authors report on the generation of a biomarker of aging from the study of proteins secreted by senescent cells. Low cost assays that map closely to biological age, the burden of damage, are a potentially useful tool for research and development of rejuvenation therapies. This biomarker is likely not general enough for that role; the accumulation of senescent cells with age in tissues throughout the body is just one of a number of mechanisms important in degenerative aging. It is always good to have further evidence that senescent cells are important in aging, to add to the very compelling animal studies that demonstrate rejuvenation when senescent cells are selectively destroyed, but an assay that reflects senescent cell burden is probably not helpful in the assessment of a candidate rejuvenation therapy that targets other mechanisms of aging.

Cells become senescent constantly, at all ages, largely somatic cells hitting the Hayflick limit on cellular replication. Cells also enter senescence when damaged, or in response to a toxic environment, or to aid in wound healing. That damaged cells become senescent helps to suppress cancer risk. This is all beneficial, so long as the senescent cells are promptly destroyed. A senescent cell releases into the surrounding environment a potent mix of molecules known as the senescence-associated secretory phenotype (SASP). The SASP rouses the immune system to inflammation, remodels tissue structure, and changes cell behavior, among other effects. This is beneficial in the short term, but becomes very damaging when sustained for the long-term. The lasting inflammation and disruption of tissue structure caused by senescent cells lingering in old tissues contributes meaningfully to the onset and progression of many age-related diseases.

The senescence-associated secretome as an indicator of age and medical risk

Aging is the strongest risk factor for the majority of chronic diseases. Recent scientific advances have led to the transformative hypothesis that interventions targeting the fundamental biology of aging have the potential to delay, if not prevent, the onset of age-associated conditions and extend human health span. Notably, there is now compelling evidence that cellular senescence, a state of stable growth arrest caused by diverse forms of cellular and molecular damage, contributes to aging, in part, through the senescence-associated secretory phenotype (SASP). Senescent cells accumulate with advancing age. Preclinical studies in rodents have established that transgenic strategies and drugs that selectively kill senescent cells improve numerous yet pathologically distinct conditions of aging.

Dramatic variability is inherent to aging. Many older adults of a given chronological age experience multiple chronic conditions and functional limitations, while paired-age counterparts may have low or no disease burden and comparatively greater functional independence. Advanced biological age may be linked to a greater burden of senescent cells in one or multiple organs. Core properties of senescent cells include upregulation of cyclin-dependent kinase inhibitors, morphological changes, activation of anti-apoptosis pathways, and a SASP composed of cytokines, chemokines, matrix remodeling proteins, and growth factors.

Senescent cell properties can be quantified in isolated tissues; however, this poses practical challenges for human application. Since the SASP is a key pathogenic feature of senescent cells, leveraging the circulating SASP as an indicator of systemic senescent cell burden may offer considerable utility. In clinical research, it can help identify persons who may be most responsive to emerging therapies and serve as surrogate endpoints in associated clinical trials. In clinical practice, SASP quantification may identify persons of advanced biological age and guide clinical decision making. We hypothesize that SASP abundance may be associated with chronological aging and accelerated biological aging.

We tested whether circulating concentrations of SASP proteins reflect age and medical risk in humans. We first screened senescent endothelial cells, fibroblasts, preadipocytes, epithelial cells, and myoblasts to identify candidates for human profiling. We then tested associations between circulating SASP proteins and clinical data from individuals throughout the life span and older adults undergoing surgery for prevalent but distinct age-related diseases. A community-based sample of people aged 20-90 years was studied to test associations between circulating SASP factors and chronological age. A subset of this cohort aged 60-90 years and separate cohorts of older adults undergoing surgery for severe aortic stenosis or ovarian cancer were studied to assess relationships between circulating concentrations of SASP proteins and biological age (determined by the accumulation of age-related health deficits) and/or postsurgical outcomes.

We showed that SASP proteins were positively associated with age, frailty, and adverse postsurgery outcomes. A panel of 7 SASP factors composed of growth differentiation factor 15 (GDF15), TNF receptor superfamily member 6 (FAS), osteopontin (OPN), TNF receptor 1 (TNFR1), ACTIVIN A, chemokine (C-C motif) ligand 3 (CCL3), and IL-15 predicted adverse events markedly better than a single SASP protein or age. Our findings suggest that the circulating SASP may serve as a clinically useful candidate biomarker of age-related health and a powerful tool for interventional human studies.

T cells of the adaptive immune system collectively become less functional with age. The immune system as a whole becomes more inflammatory and less effectively, a state described by the terms inflammaging and immunosenescence. Researchers here note that T cells struggle to survive in the aged environment, and are as a consequence metabolically inefficient. Their efforts are going towards survival rather than the activities of immune surveillance. The degree to which this contributes to immunosenesence versus other factors is an open question.

In a recent study, researchers outline that the increased metabolism of T cells observed with advanced age was an indication that they were working harder merely to survive. This contradicts previous knowledge, which suggested an increased metabolism was indicative of T cell function, and will have implications for the development of targeted interventions such as vaccines or immunotherapies to treat age-related immune dysfunction.

T cells play an important role in the body's immune response to viral infections and tumors, but T cell immunity wanes as we age, thus increasing our susceptibility to these diseases. "We've shown that an amped-up metabolism, rather than arming cells to fight pathogens better, is associated with T cell survival over a lifespan. The cells need to substantially increase their metabolism just to survive in the relatively hostile environment of the elderly. This work is important because one of the hallmarks of immune aging is the loss of T cells. Ultimately we want to support healthy ageing by designing ways to improve T cell metabolism during cell-based immunotherapies such as CAR T cell therapy, and boosting T cell activation in new vaccines.

Link: https://www.eurekalert.org/pub_releases/2020-06/mu-tci060420.php

DNA sequencing over generations can be used to determine individual rates of germline mutation, as mutations present in the child but not the parent must have occurred in the parent germline. Stochastic nuclear DNA damage takes place over the course of aging, and evidence suggests that this correlates with the pace at which a person is aging. While nuclear DNA damage determines cancer risk, the degree to which it contributes to other forms of age-related degeneration is an open question. Only damage occurring in stem cells or progenitor cells, and that can thus spread through tissue in daughter somatic cells, seems likely to have a meaningful effect. Interventions such as calorie restriction, known to slow aging and extend life in laboratory species, do slow the onset of such unrepaired damage to nuclear DNA. All of this makes the research noted here quite interesting.

Scientists have long known that DNA damage constantly occurs in the body. Typically, various mechanisms repair this damage and prevent potentially harmful mutations. As we get older, these mechanisms become less efficient and more mutations accumulate. Older parents, for instance, tend to pass on more genetic mutations through their germline (egg and sperm) to their children than younger parents.

Researchers theorized that these mutations could be a biomarker for rates of aging and potentially predict lifespan in younger individuals as well as fertility in women. The researchers sequenced DNA from 61 men and 61 women who were grandparents in 41 three-generational families. The families were part of the Centre d'Etude du Polymorphisme Humain (CEPH) consortium, which was central to many key investigations that have contributed toward a modern understanding of human genetics.

The researchers analyzed blood DNA sequences in trios consisting of pairs of grandparents from the first generation and one of their children from the second generation. That's because germline mutations are passed on to their offspring. Mutations found in the child's blood DNA that were not present in either parent's blood DNA were then inferred to have originated in the parents' germlines. The researchers were then able to determine which parent each germline mutation came from, and, therefore, the number of such mutations each parent had accumulated in egg or sperm by the time of conception of the child.

Knowing that allowed the researchers to compare each first-generation parent to others of the same sex and estimate their rate of aging. "Compared to a 32-year-old man with 75 mutations, we would expect a 40-year-old with the same number of mutations to be aging more slowly. We'd expect him to die at an older age than the age at which the 32-year-old dies." The scientists found that mutations began to occur at an accelerating rate during or soon after puberty, suggesting that aging begins in our teens. Some young adults acquired mutations at up to three times the rate of others. After adjusting for age, the researchers determined that individuals with the slowest rates of mutation accumulation were likely to live about five years longer than those who accumulated mutations more rapidly.

Link: https://healthcare.utah.edu/publicaffairs/news/2020/06/06-aging.php

The evidence to date strongly suggests that environmental factors determine longevity for the vast majority of people. If there are significant longevity-affecting gene variants out there, then they have small and unreliable effects (APOE), or are restricted to tiny lineages (SERPINE1), or both. The overwhelming majority of contributions to longevity emerge from lifestyle choices relating to weight, exercise, smoking, and so forth, and exposure to persistent pathogens such as cytomegalovirus. In the near future we'll add access to rejuvenation therapies to this list, but that is only just getting underway now and isn't yet relevant to epidemiological studies of older people.

Today's open access paper on environment and lifestyle choice versus the odds of becoming a centenarian is interesting for showing a few correlations that stand in opposition to the rest of the literature. For example, lower educational achievement and being widowed correlates with greater odds of living to 100 in this study. This is perhaps a good example of the perils of epidemiology, and particularly the challenges inherent in reasoning about epidemiological data. One should never take any one paper at face value without considering the rest of the literature, and one should bear in mind that different views (just people in one geographic area) or slices of data (just older people) may well produce opposing results.

Environmental Correlates of Reaching a Centenarian Age: Analysis of 144,665 Deaths in Washington State for 2011-2015

The survival probability of becoming a centenarian has been shown to be multifactorial. The rapid increase in the odds of living to 100 years of age is largely due to substantial advancements in medicine and public health that decreased the burden of disease. Genetic factors, including genes in several pathways influencing longevity, such as inflammation and immunity, have also been explored. These studies have shown that longevity is likely to be a polygenic trait, but aging has been attributed to be only 20-35% heritable. Social and environmental factors, such as high educational attainment and socioeconomic status, also significantly contribute to longevity.

This study aimed to examine the likelihood of becoming a centenarian for adults aged 75 and above in Washington State and to identify social and environmental correlates of healthy aging and longevity. In addition, we identified geographic clusters within Washington State where individuals are more likely to become centenarians. Models were adjusted for sex, race, education, marital status, and neighborhood level social and environmental variables at the block group level. In the adjusted model, increased neighborhood walkability, lower education level, higher socioeconomic status, and a higher percent of working age population were positively associated with reaching centenarian age. Being widowed, divorced/separated, or never married were also positively correlated compared to being married. Additionally, being white or female were positively correlated with reaching centenarian status.

Surprisingly, education was found to be negatively associated with becoming a centenarian. In recent studies, higher education levels have been strongly associated with lower mortality. Higher academic level indicates employment opportunities and lifestyles associated with factors such as socioeconomic status, social connections, availability and knowledge of health resources, health behaviors (e.g., not smoking), and critical thinking skills applied to managing health problems.

Rapid advances in educational attainment in the last few generations may explain, in part, the lack of a positive association between educational attainment and becoming a centenarian in our study. In this regard, in 1950, only 34.3% of the U.S. population above the age of 25 had a high school diploma, a figure that increased to more than 80% by 2000. More recent studies have demonstrated increasing declines in mortality with education, suggesting that education is less of a factor in determining longevity in older populations.

Another unexpected finding was that compared to married older adults, those who never married, or were widowed, or divorced/separated were more likely to become centenarians. Being widowed showed the greatest benefit, with never having married coming second, and being divorced/separated showing the least benefit. Decades of work have consistently observed that marriage is associated with longer survival than being divorced or never having married. However, this study specifically focused on those aged 75 and above, so the selection aspect and some of the protective factors may not be as relevant.

Many studies have not explored the effects of marital status on health at older ages specifically. In this study, the finding of a much greater likelihood of becoming a centenarian for those who are widowed may be partially explained by the fact that those who lost their spouses earlier in life may no longer experience the stresses associated with the traumatic event. This line of reasoning may also contribute to the findings around being divorced/separated leading to a greater likelihood of becoming a centenarian, which is not generally consistent with prior research.

Chimeric antigen receptor (CAR) T cell therapies target specific surface features on other cells by providing T cells with a way to recognize that feature - the CAR. T cells so equipped will selectively destroy other cells with the target surface feature. To produce a CAR T cell therapy, a patient's T cells are taken, genetically engineered to introduce the CAR, expanded, and then reintroduced. This is presently used as a form of cancer therapy. Given a surface feature sufficiently specific to senescent cells, CAR T cell immunotherapy can be turned into a senolytic treatment, however. Senescent cell accumulation is one of the important causes of degenerative aging, and effective clearance of senescent cells is a form of rejuvenation. Researchers here claim to have identified a suitably specific surface marker of senescence, and use it to demonstrate benefits in mice via CAR T cell therapy. It will be interesting to see how this develops.

Cellular senescence is characterized by stable cell-cycle arrest and a secretory program that modulates the tissue microenvironment. Physiologically, senescence serves as a tumour-suppressive mechanism that prevents the expansion of premalignant cells and has a beneficial role in wound-healing responses. Pathologically, the aberrant accumulation of senescent cells generates an inflammatory milieu that leads to chronic tissue damage and contributes to diseases such as liver and lung fibrosis, atherosclerosis, diabetes, and osteoarthritis. Accordingly, eliminating senescent cells from damaged tissues in mice ameliorates the symptoms of these pathologies and even promotes longevity.

Here we test the therapeutic concept that chimeric antigen receptor (CAR) T cells that target senescent cells can be effective senolytic agents. We identify the urokinase-type plasminogen activator receptor (uPAR) as a cell-surface protein that is broadly induced during senescence and show that uPAR-specific CAR T cells efficiently ablate senescent cells in vitro and in vivo. CAR T cells that target uPAR extend the survival of mice with lung adenocarcinoma that are treated with a senescence-inducing combination of drugs, and restore tissue homeostasis in mice in which liver fibrosis is induced chemically or by diet. These results establish the therapeutic potential of senolytic CAR T cells for senescence-associated diseases.

Link: https://doi.org/10.1038/s41586-020-2403-9

Living a sedentary lifestyle is known to be harmful to long term health, raising the risk of age-related disease and mortality. Researchers here show that a sedentary life specifically increases cancer mortality, and does so independently of other factors. This is one of many, many reasons to maintain a regular schedule of exercise.

In the first study to look at objective measures of sedentary behavior and cancer mortality, researchers found that greater inactivity was independently associated with a higher risk of dying from cancer. The most sedentary individuals had an 82% higher risk of cancer mortality compared to the least sedentary individuals. Researchers also found that replacing 30 minutes of sedentary time with physical activity was associated with a 31% lower risk of cancer death for moderate-intensity activity, such as cycling, and an 8% lower risk of cancer death for light-intensity activity, such as walking.

This study involved a cohort of participants from the nationally representative REGARDS study, which recruited more than 30,000 U.S. adults over the age of 45 between 2003 and 2007 to study long-term health outcomes. To measure sedentary behavior, 8,002 REGARDS participants who did not have a cancer diagnosis at study enrollment wore an accelerometer on their hip during waking hours for seven consecutive days. The accelerometer data was gathered between 2009 and 2013. After a mean follow-up of 5 years, 268 participants died of cancer. Longer duration of sedentary behavior was independently associated with a greater risk of cancer death.

The study also found that engaging in either light or moderate to vigorous physical activity made a difference. Investigators assessed sedentary time, light-intensity physical activity (LIPA) and moderate to vigorous physical activity (MVPA) in the same model and found that LIPA and MVPA, not sedentary behavior, remained significantly associated with cancer mortality. "From a practical perspective, this means that individuals who replaced either 10 to 30 minutes of sedentary time with either LIPA or MVPA had a lower risk of cancer mortality in the REGARDS cohort."

Link: https://www.mdanderson.org/newsroom/study-shows-sedentary-behavior-independently-predicts-cancer-mortality.h00-159382734.html

Cyclodextrins bind to cholesterol. This aspect of their biochemistry has been used by the Underdog Pharmaceuticals team to produce a cyclodextrin that binds the form of toxic oxidized cholesterol known as 7-ketocholesterol. 7-ketocholesterol builds up with age and is implicated in a range of age-related conditions, particularly atherosclerosis, as altered cholesterols cause dysfunction in the macrophage cells responsible for removing cholesterols and other lipids from blood vessel walls. The outcome is the creation of fatty lesions that narrow and weaken blood vessels in older individuals, an ultimately fatal condition. Removing 7-ketocholesterol and other problem altered cholesterols is a promising approach to therapy.

In today's research materials, the authors report on a different way to use an existing cyclodextrin to tackle atherosclerosis. They encapsulate molecules of the cyclodextrin and a statin in nanoparticles. The nanoparticles release the statin in atherosclerotic lesions, and take in cholesterol molecules that bind to the cyclodextrin. This sequestering of cholesterol aids macrophages in their work, most likely through binding some fraction of the altered cholesterols that cause issues, and results in a sizable reduction in the lesion size in a mouse model. Around a 50% reversal of atherosclerotic lesions is about the best that has been achieved in mice, and this is in that ballpark, averaged over different portions of the aorta. We might take this as helpful support for the Underdog Pharmaceuticals approach.

New nanoparticle drug combination for atherosclerosis

Physicochemical cargo-switching nanoparticles (CSNP) can help significantly reduce cholesterol and macrophage foam cells in arteries, which are the two main triggers for atherosclerotic plaque and inflammation. The CSNP-based combination drug delivery therapy was proved to exert cholesterol-lowering, anti-inflammatory, and anti-proliferative functions of cyclodextrin and statin, two common medications for treating and preventing atherosclerosis.

Researchers reported that the polymeric formulation of cyclodextrin with a diameter of approximately 100 nm can accumulate within the atherosclerotic plaque and effectively reduce the plaque even at lower doses, compared to cyclodextrin in a non-polymer structure. Moreover, although cyclodextrin is known to have a cytotoxic effect on hair cells in the cochlea, which can lead to hearing loss, cyclodextrin polymers developed by the research group exhibited a varying biodistribution profile and did not have this side effect.

The researchers exploited the fact that cyclodextrin and statin form the cyclodextrin-statin self-assembly drug complex, based on previous findings that each drug can exert local anti-atherosclerosis effect within the plaque. The complex formation processes were optimized to obtain homogeneous and stable nanoparticles with a diameter of about 100 nm for systematic injection. The therapeutic synergy of cyclodextrin and statin could reportedly enhance plaque-targeted drug delivery and anti-inflammation. Cyclodextrin led to the regression of cholesterol in the established plaque, and the statins were shown to inhibit the proliferation of macrophage foam cells.

Affinity-Driven Design of Cargo-Switching Nanoparticles to Leverage a Cholesterol-Rich Microenvironment for Atherosclerosis Therapy

Atherosclerotic plaques exhibit high deposition of cholesterol and macrophages. These are not only the main components of the plaques but also key inflammation-triggering sources. However, no existing therapeutics can achieve effective removal of both components within the plaques. Here, we report cargo-switching nanoparticles (CSNP) that are physicochemically designed to bind to cholesterol and release anti-inflammatory drug in the plaque microenvironment. CSNP have a core-shell structure with a core composed of an inclusion complex of methyl-β-cyclodextrin (cyclodextrin) and simvastatin (statin), and a shell of phospholipids.

Upon interaction with cholesterol, which has higher affinity to cyclodextrin than statin, CSNP release statin and scavenge cholesterol instead through cargo-switching. CSNP exhibit cholesterol-sensitive multifaceted anti-atherogenic functions attributed to statin release and cholesterol depletion in vitro. In mouse models of atherosclerosis, systemically injected CSNP target atherosclerotic plaques and reduce plaque content of cholesterol and macrophages, which synergistically leads to effective prevention of atherogenesis and regression of established plaques. These findings suggest that CSNP provide a therapeutic platform for interfacing with cholesterol-associated inflammatory diseases such as atherosclerosis.

It has been a while now since the development of the first epigenetic clock, a weighted combination of DNA methylation sites that correlates tightly with chronological age. More interesting is that epigenetic ages higher than chronological ages correlate with age-related mortality, as well as risk and progression of numerous age-related diseases. This has inspired all sorts of similar efforts to produce clocks based on the wealth of data that can be assessed from blood, tissue, and other samples. Here, researchers discuss their work on a clock derived from the metabolome, the diverse collection of metabolites present in a biological sample. This research into biomarkers of aging is hoped to lead to a fast, cheap, and effective method to assess potential rejuvenation therapies: test shortly before and shortly after treatment, and compare. We're not there yet, however.

Since aging is a process that affects almost all tissues and organs and involves crosstalk between multiple physiological systems, there has been increased research into composite markers of aging, involving multiple parameters. Biological age scores have been developed by combining established clinical biomarkers and have been associated with measures of functional decline such as cognitive ability.

Modern "omics" platforms have provided new opportunities for the systematic and agnostic assessment of biological aging. Analysis of genome-wide DNA methylation, mRNA, and miRNAs has allowed the development of multi-parameter "omic clocks," built upon molecular changes that tick at an average rate consistent with chronological age. DNA methylation age acceleration, defined as having a greater DNA methylation age than chronological age (i.e., a faster than average "ticking rate"), is associated with multiple noncommunicable disease (NCD) risk factors and predictive of aging outcomes such as frailty, cognitive decline, and all-cause mortality.

Metabolomics, the profiling of small molecules, is a promising technology for the comprehensive assessment of biological aging. As the final product of cellular metabolism, metabolites may provide a more complete picture of biological processes and a stronger phenotypic representation than other "omic profiles." Although metabolomic studies have reported strong associations between metabolites and age, these have been of limited sample size.

We developed a model of age based on untargeted metabolic profiling across multiple platforms, including nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry in urine and serum, within a large sample (N = 2,239) from the UK Airwave cohort. We validated a subset of model predictors in a Finnish cohort including repeat measurements from 2,144 individuals. We investigated the determinants of accelerated aging, including lifestyle and psychological risk factors for premature mortality.

The metabolomic age model was well correlated with chronological age (mean r = .86 across independent test sets). Increased metabolomic age acceleration (mAA) was associated after false discovery rate (FDR) correction with overweight/obesity, diabetes, heavy alcohol use, and depression. DNA methylation age acceleration measures were uncorrelated with mAA. Increased DNA methylation phenotypic age acceleration (N = 1,110) was associated after FDR correction with heavy alcohol use, hypertension, and low income. In conclusion, metabolomics is a promising approach for the assessment of biological age and appears complementary to established epigenetic clocks.

Link: https://doi.org/10.1111/acel.13149

There is a well-established web of correlations between life expectancy, wealth, intelligence, education, and social status. It is challenging to pick apart the underlying mechanisms, however, given demographic and epidemiological data as a starting point. For example, a slow debate is presently underway regarding the degree to which the correlation between intelligence and life expectancy has genetic origins, in that more physically robust people tend to be more intelligent, versus the more obvious suggestion that intelligent people tend to take better care of their health. That low socioeconomic status correlates with an accelerated onset of age-related declines in health also has the look of being explicable through worse maintenance of health over the long term: the usual triad of diet and weight, exercise, and smoking. That said, this study controlled for smoking, which makes it more interesting than the usual such work.

Lower socioeconomic status (SES) is a determinant of many of the health problems that emerge at older ages. The extent to which lower SES is associated with faster decline in age-related functions and phenotypes independently of health conditions is less clear. This study demonstrates that lower SES (defined by wealth) is related to accelerated decline over 6 to 8 years in 16 outcomes from physical, sensory, physiological, cognitive, emotional, and social domains, independently of diagnosed health conditions, self-rated health, education, and other factors. It provides evidence for the pervasive role of social circumstances on core aging processes and suggests that less affluent sectors of society age more rapidly than more privileged groups.

Aging involves decline in a range of functional abilities and phenotypes, many of which are also associated with socioeconomic status (SES). Here we assessed whether lower SES is a determinant of the rate of decline over 8 years in six domains - physical capability, sensory function, physiological function, cognitive performance, emotional well-being, and social function - in a sample of 5,018 men and women aged 64.44 (standard deviation 8.49) years on average at baseline. Wealth was used as the marker of SES, and all analyses controlled for age, gender, ethnicity, educational attainment, and long-term health conditions.

Lower SES was associated with greater adverse changes in physical capability (grip strength, gait speed, and physical activity), sensory function (sight impairment), physiological function (plasma fibrinogen concentration and lung function), cognitive performance (memory, executive function, and processing speed), emotional well-being (enjoyment of life and depressive symptoms), and social function (organizational membership, number of close friends, volunteering, and cultural engagement). Effects were maintained when controlling statistically for other factors such as smoking, marital/partnership status, and self-rated health and were also present when analyses were limited to participants aged ≤75 years of age. We conclude that lower SES is related to accelerated aging across a broad range of functional abilities and phenotypes independently of the presence of health conditions and that social circumstances impinge on multiple aspects of aging.

Link: https://doi.org/10.1073/pnas.1915741117

Research into the effects of the gut microbiome on health and aging is presently flourishing. Scientists are identifying meaningful changes in microbial populations that take place with age, as well as metabolites generated by gut microbes that favorably influence health, such as indoles, butyrate, propionate, and so forth. With advancing age, the balance of microbial populations shifts from beneficial to harmful. The production of beneficial metabolites decreases. Microbes invade gut tissue to produce a state of chronic inflammation that spreads to accelerate the onset and progression of age-related disease throughout the body. The size of the contribution of the gut microbiome to the progression of aging is up for debate, but based on evidence from animal models it isn't unreasonable to guess at it being in the same ballpark as the effects of exercise.

There are many possible causes of the age-related deterioration of the gut microbiome. Dietary changes, lesser degrees of exercise, dysfunction in intestinal tissues, the decline of immune function. The immune system plays a role in gardening the microbes of the gut, as illustrated by the fact that beneficial changes in the gut microbe can be produced via forms of immunization against bacterial proteins.

Regardless of cause, a range of strategies might be employed to readjust a dysfunctional gut microbiome to produce a better outcome for the individual. For example, fecal microbiata transplantation from young to old has been shown to extend life in short lived killifish. In principle similar effects could be achieved with aggressive use of probiotics, or methods of selective destruction of harmful microbes. The approach noted in today's research materials is an example of the latter approach. Researchers have identified molecules that are harmless to cells, but suppress growth in some species of harmful gut microbes. The result is improved health in an animal model of a poor diet.

Molecules that reduce 'bad' gut bacteria reverse narrowing of arteries in animal study

The gut microbiome, which includes hundreds of bacterial species, evolved long ago as part of a fundamental symbiosis: The bacteria get a place to live and plenty to eat, and in return they assist their animal hosts, largely by helping them digest food. Scientists have learned that this symbiosis can have a downside for the bacteria's human hosts. When people overuse antibiotics or consume "Western" diets rich in carbs, fats and sugar, the gut microbiome can be altered in ways that promote disease. Indeed, it now appears that the increased risks of obesity, diabetes, hypertension, and atherosclerosis that are conferred by the Western diet are due in part to adverse changes in the microbiome.

That recognition has led researchers to look for ways to remodel the microbiome. "Our approach, using small molecules called cyclic peptides, is inspired by nature. Our cells naturally use a diverse collection of molecules including antimicrobial peptides to regulate our gut microbe populations." the team already had a small collection of cyclic peptides that had been made using chemistry techniques. For the study, they set up a screening system to determine if any of those peptides could beneficially remodel the mammalian gut microbiome by suppressing undesirable gut bacterial species.

Using mice that are genetically susceptible to high cholesterol, they fed the animals a Western-type diet that swiftly and reliably produces high blood cholesterol and atherosclerosis, as well as adverse shifts in the gut microbiome. The researchers then sampled the animals' gut contents and applied a different cyclic peptide to each sample. A day later, they sequenced the bacterial DNA in the samples to determine which peptides had shifted the gut microbiome in the desired direction.

The scientists soon identified two peptides that had significantly slowed the growth of undesirable gut bacteria, shifting the species balance closer to what is seen in mice that are fed a healthier diet. Using these peptides to treat atherosclerosis-prone mice that were eating a high-fat Western diet, they found striking reductions in the animals' blood levels of cholesterol compared to untreated mice - about 36 percent after two weeks of treatment. They also found that after 10 weeks, the atherosclerotic plaques in the arteries of the treated mice were about 40 percent reduced in area, compared to those in untreated mice.

Directed remodeling of the mouse gut microbiome inhibits the development of atherosclerosis

The gut microbiome is a malleable microbial community that can remodel in response to various factors, including diet, and contribute to the development of several chronic diseases, including atherosclerosis. We devised an in vitro screening protocol of the mouse gut microbiome to discover molecules that can selectively modify bacterial growth. This approach was used to identify cyclic d,l-α-peptides that remodeled the Western diet (WD) gut microbiome toward the low-fat-diet microbiome state.

Daily oral administration of the peptides in WD-fed LDLr-/- mice reduced plasma total cholesterol levels and atherosclerotic plaques. Depletion of the microbiome with antibiotics abrogated these effects. Peptide treatment reprogrammed the microbiome transcriptome, suppressed the production of pro-inflammatory cytokines (including interleukin-6, tumor necrosis factor-α, and interleukin-1β), rebalanced levels of short-chain fatty acids and bile acids, improved gut barrier integrity and increased intestinal T regulatory cells. Directed chemical manipulation provides an additional tool for deciphering the chemical biology of the gut microbiome and might advance microbiome-targeted therapeutics.

The accumulation of senescent cells in tissues throughout the body is a cause of aging, but it is also a phenomenon that occurs in cell cultures. Senescent cells do not replicate and secrete a potent inflammatory mix of signal molecules that degrades tissue function. Senescence in cells expanded in culture is a challenge to the efficacy of cell therapies, and may go some way towards explaining the unreliability in benefits obtained from clinic to clinic and treatment to treatment. First generation mesenchymal stem cell therapies are now widely employed, and researchers are starting to give greater attention to ways to minimize senescence in the cells delivered to patients.

Mesenchymal stem cells (MSCs) are multipotent cells capable of self-renewal and differentiation. There is increasing evidence of the therapeutic value of MSCs in various clinical situations, however, these cells gradually lose their regenerative potential with age, with a concomitant increase in cellular dysfunction. Stem cell aging and replicative exhaustion are considered as hallmarks of aging and functional attrition in organisms. MSCs do not proliferate infinitely but undergo only a limited number of population doublings before becoming senescent. This greatly hinders their clinical application, given that cultures must be expanded to obtain a sufficient number of cells for cell-based therapy.

Strategies allowing the generation of large numbers of MSCs that have retained their stemness are needed for clinical applications. Induced pluripotent stem cell (iPSC)-derived MSCs (iMSCs) can be passaged more than 40 times without exhibiting features of senescence. iMSCs retain a donor-specific DNA methylation profile while tissue-specific, senescence-associated, and age-related patterns are erased during reprogramming. Recent studies have demonstrated that iMSCs have superior regenerative capacity compared to tissue-derived MSCs in preclinical degenerative disease models. However, the generation of iMSCs from iPSCs requires a significant degree of molecular manipulation, and there are safety concerns regarding the self-renewal and pluripotency of iPSC-derived cells after in vivo transplantation.

Aging is not a passive or random process but can be modulated through several key signaling molecules/pathways. Identification of age-related coordinating centers can provide novel targets for therapeutic interventions. Sirtuins (SIRTs) are a class of highly conserved nicotinamide adenine dinucleotide-dependent protein deacylases. The role of SIRTs in aging is related to their regulation of energy metabolism, cell death, and circadian rhythm and maintenance of cellular and mitochondrial protein homeostasis. Overexpression of SIRTs has been investigated as a potential strategy for preventing MSC aging. For instance, SIRT3 expression in MSCs decreased with prolonged culture and its overexpression in later-passage cells restored differentiation capacity and reduced aging-related senescence.

Genetic engineering has been used to slow MSC aging. Besides SIRTs, several molecules have been identified as potential targets for interventions to prevent senescence. Ectopic expression of telomerase reverse transcriptase in MSCs extended their replicative lifespan, which preserved a normal karyotype, promoted telomere elongation, and abolished senescence without loss of differentiation potential. Introduction of Erb-B2 receptor tyrosine kinase 4 (ERBB4) in aged MSCs conferred resistance to oxidative stress-induced cell death and rescued the senescence phenotype. Knocking down macrophage migration inhibitory factor (MIF) in young MSCs induced senescence; conversely, its overexpression in aged MSCs rejuvenated the cells by activating autophagy. However, the risk of malignant transformation remains a major barrier for the use of genetics-based approaches in clinical practice.

Link: https://doi.org/10.3389/fcell.2020.00258

The interaction between the immune system and tumor is meaningfully different in young and old individuals. The aging of the immune system makes near everything worse in health and physiology. It greatly affects risk of cancer, in the sense of determining whether pre-cancerous cells are eliminated before they can gain a foothold. It also affects the distribution of cancer types, for reasons that are not fully explored. Further, and as discussed here, it affects the efforts of the immune system to destroy an established tumor.

Advanced age is strongly correlated with both increased cancer incidence and general immune decline. The immune tumor microenvironment (ITME) has been established as an important prognostic of both therapeutic efficacy and overall patient survival. Thus, age-related immune decline is an important consideration for the treatment of a large subset of cancer patients. Current studies of aging-related immune alterations are predominantly performed on non-cancerous tissue, requiring additional study into the effects of age on tumor immune infiltration.

We leverage large scale transcriptional data sets from The Cancer Genome Atlas and the Genotype-Tissue Expression project to distinguish normal age-related immune alterations from age-related changes in tumor immune infiltration. We demonstrate that while there is overlap between the normal immune aging phenotype and that of the ITME, there are several changes in immune cell abundance that are specific to the ITME, particularly in T cell, NK cell, and macrophage populations.

These results suggest that aged immune cells are more susceptible to tumor suppression of cytotoxic immune cell infiltration and activity than normal tissues, which creates an unfavorable ITME in older patients in excess of normal immune decline with age and may inform the application of existing and emerging immunotherapies for this large population of patients. We additionally identify that age-related increases in tumor mutational burden are associated with decreased DNA methylation and increased expression of the immune checkpoint genes PDL1, CD80, and LAG3 which may have implications for therapeutic application of immune checkpoint blockade in older patients.

Link: https://doi.org/10.1101/2020.06.08.140764

Cells in the body become senescent constantly, in response to reaching the Hayflick limit on replication, to DNA damage, to a toxic local environment, to injury. A senescent cell grows large, ceases replication, and secretes a potent mix of signals, the senescence-associated secretory phenotype (SASP). The SASP rouses the immune system into an inflammatory state, disrupts tissue maintenance and structure, and encourages other cells to also become senescent. In the short term this is a necessary part of wound healing and cancer suppression. If maintained for the long term, the SASP becomes very harmful, however.

Near all senescent cells cells are rapidly destroyed, either by programmed cell death or by the immune system. This is a requirement to maintain functional tissues, given the harms produced by a sustained SASP. Unfortunately senescent cells accumulate with age. It remains unclear as to the degree to which this is an imbalance between creation and destruction versus a small fraction of senescent cells being resistant to clearance. It is certainly the case that clearance mechanisms appear to slow down in older individuals, while on the other hand some senescent cells find ways to evade the immune system.

In today's open access paper, researchers outline what is known of the role of the immune system in the clearance of senescent cells. It is likely that the characteristic age-related decline in immune function that takes place with advancing age is the most important determinant of the significant growth in the senescent cell burden in tissues in later life. This is one the many ways in which immune aging sabotages health and reduces life span.

Role of immune cells in the removal of deleterious senescent cells

Cellular senescence is an essentially irreversible arrest of cell proliferation coupled to a complex senescence-associated secretory phenotype (SASP). The SASP is conserved between mice and humans, and even to some extent between mammals and insects. Its components include growth factors, chemokines and cytokines, proteases, bioactive lipids and extracellular vesicles, many of which are pro-inflammatory. The number of senescent cells increases with age in most tissues, although they rarely exceed a few percent. Nonetheless, mounting evidence suggests that senescent cells can drive a surprisingly diverse array of aging phenotypes and diseases, mainly through the SASP. The presence of senescent cells also exacerbates several diseases including, but not limited to, osteoarthritis, osteoporosis, atherosclerosis, Parkinson's disease, and Alzheimer's disease.

Importantly, eliminating senescent cells in transgenic mouse models often delays age-related tissue dysfunction and increases health span. Furthermore, several laboratories are developing new classes of drugs termed senolytics, which kill senescent cells, or senomorphics, which alleviate SASP effects. These drugs can help maintain homeostasis in aged or damaged tissues, and postpone or ameliorate many age-related pathologies.

Current thinking is that the short-term presence of senescent cells is beneficial, largely by adjusting the plasticity of neighboring cells, but that their prolonged presence can be deleterious. The timely clearance of senescent cells is required to maintain tissue and organismal homeostasis. Although cellular senescence has been studied in detail in the context of disease, the interaction of senescent cells with immune cells have been less thoroughly investigated. Due in large measure to the SASP, senescent cells likely interact extensively with the immune system. The production and secretion of SASP factors (resulting in local inflammation) can be a potent means to recruit immune cells. The SASP recruits macrophages, natural killer (NK) cells, neutrophils, and T lymphocytes, which eliminate them, but senescent cells can also interact with immune cells to avoid elimination.

There are currently several immune cell therapies for cancer under development or approved, which could potentially be redesigned to target senescent cells. Chimeric antigen receptor (CAR) T cell therapy has been successful in recent years for treating diseases such as cancer. CAR-T cell therapy uses autologous cells that are genetically modified ex vivo to encode a synthetic receptor that binds a known antigen. The modified cells are then infused back into the patient to kill the target cells. Evidence that there are senescent-specific surface markers is spotty, and specificity needs further validation. Nonetheless, once a good target has been identified, it can be used to create a CAR-T cell.

As senescent cells are naturally targeted for elimination by NK cells, it could be beneficial to use NK cells to eliminate persistent pro-inflammatory senescent cells, particularly as they accumulate during aging. Even though technical, logistical, and financial challenges are still limiting factors for applications of circulating NK cells as promising cancer therapies, over the past decade, several studies demonstrated the safety and efficacy of allogeneic NK cells against various hematological malignancies. The same technology could be used to target senescent cells by NK cells.

Macrophages can eliminate senescent cells. Transplanted macrophages can migrate into tissues and become tissue-resident with much longer half-lives and self-renewal abilities. Because macrophages are phenotypically plastic, and cancer cells often express a "don't eat me" signal, macrophage cell therapies have not been very successful in treating cancer. Whether this limitation poses a difficulty in using macrophages against senescent cells is not clear. NFκB-dependent pro-inflammatory signaling appears to upregulate the "don't eat me" marker CD47, at least in some cancers, facilitating their escape from immune surveillance. Senescent cells generally upregulate NFκB activity, which can activate CD47 transcription.

A better understanding of the interplay between immune cells and senescent cells would illuminate changes that happen during aging, and also speed the development of novel therapeutic interventions for eliminating deleterious senescent cells. Different approaches could be formulated to remove senescent cells using the natural ability of immune cells. What is needed now is a more thorough understanding of the heterogeneity of senescent cells and of the specific targets for immune cells.

Osteoporosis is the name given to the advanced stages of the characteristic age-related loss of bone strength and density. Bone tissue is constantly remodeled, created by osteoblasts and broken down by osteoclasts. With advancing age, the activity of osteoclasts begins to dominate, and thus bone becomes ever weaker and lighter, with eventually disastrous consequences. There are many possible contributing causes for this imbalance between cell types, most of which are present in all older individuals. It is therefore interesting to speculate on why only some people progress to clinical osteoporosis. Hence studies of the sort noted here, in which researchers attempt to pick apart the complexities of the disease state, in search of noteworthy differences between older individuals with and without clinical osteoporosis.

Osteoporosis is a metabolic disease characterized by decreased bone mass per unit volume, despite the bone tissue having normal calcification and a normal ratio of calcium salt and matrix. As one of the most commonly occurring chronic diseases among the elderly, osteoporosis has become a serious problem for public health care systems. The pathogenesis of osteoporosis has not yet been fully elucidated. Factors that inhibit osteogenesis, promote bone resorption, or cause bone microstructural destruction may play a role in the development of osteoporosis, and a variety of genes may be directly or indirectly involved.

In the present study, we applied bioinformatic analysis of an osteoporosis microarray dataset retrieved from the Gene Expression Omnibus (GEO) to explore the mechanisms underlying osteoporosis. We analyzed the interactions among involved proteins and ranking the top 10 hub genes. The identified hub genes were TP53, MAPK1, CASP3, CTNNB1, CCND1, NOTCH1, CDK1, IGF1, ERBB2, and CYCS. Moreover, we found that nearly all of the top 10 hub genes were involved in the top five enriched Gene Ontology terms or KEGG pathways, indicating their potential roles in osteoporosis progression. Consistent with our findings, a number of studies have previously reported the involvement of TP53, MAPK1, CASP3, CTNNB1, CCND1, NOTCH1, CDK1, IGF1, ERBB2 in osteoporosis or osteogenesis.

P53 had the highest degree score in the network, indicating it may play a central role during the development of osteoporosis. P53 is encoded by the tumor suppressor gene TP53 and suppresses tumor growth by slowing cell growth and division. In the present study, it is found that serum p53 levels are increased in osteoporosis patients, and knocking down p53 partially reversed decreases in bone mineral density in vitro and in vivo. In addition, GO and KEGG enrichment analyses indicate that p53 is involved in "the cancer pathway," "proteoglycans in cancer pathway," and "P53 signaling pathway." We therefore suggest that p53 may contribute to the pathogenesis of osteoporosis via these pathways.

Link: https://doi.org/10.18632/aging.103271

Despite the challenges inherent in the practical use of epigenetic clocks based on age-related changes in DNA methylation, clinical trials are forging ahead in the employment of these clocks. The assays are cheap enough that there is a sense of "why not?" and, considered over patient populations rather than in individuals, an epigenetic age higher than chronological age correlates well with risk and progression of age-related disease. It remains problematic for any given individual to extract meaning from an epigenetic clock assay, however. It is unclear as to what exactly the measured age-related changes in DNA methylation reflect, in terms of the underlying damage and dysfunction of aging, and thus results are not yet actionable for the individual.

Geroscience is a developing discipline based on the premise that health can be improved by targeting aging. Clinical trials are underway to test the geroscience hypothesis in humans. Definitive tests of the hypothesis must demonstrate reduced rates of age-related diseases and death, but the length of time and size of trial needed to test the hypothesis are both substantial. Therefore, objective, quantifiable characteristics of the aging process - known as biomarkers - that can be tracked in clinical trials are needed for the field to progress.

Useful biomarkers should meet several criteria: i) their measurement should be reliable and feasible; ii) they should be relevant to aging; iii) they should robustly and consistently predict trial endpoints, such as functional ability, disease, or death; and iv) they should be responsive to interventions such as treatments targeting aging biology. Practically speaking, this means that a change in the level of a biomarker should parallel changes in the susceptibility to disease, age of death, or loss of function. Interventions that target aging and support the geroscience hypothesis should therefore also lead to changes in these biomarkers, which will be reflected in the incidence or severity of age-related diseases and functional decline.

Biomarkers based on DNA methylation levels look promising. Briefly, these biomarkers quantify the proportion of cells in which a gene locus is methylated. Small but consistent changes in the methylation of some loci occur in organisms with older ages, and early methods for estimating age using epigenetics took advantage of these chronologic changes. However, critics argue that while these 'clocks' may be associated with chronological age, it is uncertain whether they reflect meaningful change in the context of interventions affecting the underlying biology.

Estimators based on the levels of DNA methylation are now being developed to detect a myriad of disease states and predict mortality and adverse health events, and each is unique to its calibration method. Now researchers report the development of a new epigenetic biomarker called Dunedin Pace of Aging methylation (DunedinPoAm) that is able to detect how aging phenotypes change over time. The new biomarker relies on a composite measure called the Pace of Aging. Pace of Aging is calculated based on a number of age-related phenotypic changes that occur over time. In the new work this measure was used to calibrate and validate a DNA-wide methylation clock in four independent cohorts.

Is DunedinPoAm developed to the point where it could be relied upon as a biomarker for clinical trials targeting biological aging? DunedinPoAm appears to satisfy the criteria aside from being responsive to interventions. One of the cohorts used to validate the new approach consisted of middle-aged, non-obese adults enrolled in the CALERIE trial. This trial tested the effects of caloric restriction - an intervention that has been successful in animal models - over a period of two years. DunedinPoAm was able to predict changes in the Pace of Aging measure in the control group, but not in the group that had been calorie restricted. However, it remains to be seen whether interventions which affect aging biology change DunedinPoAm in a way that is consistent with the phenotypic changes observed in the trial. Testing the geroscience hypothesis in clinical trials is still in its early days, so it is not surprising that DunedinPoAm does not yet meet the primary criterion for an aging biomarker.

Link: https://doi.org/10.7554/eLife.58592

Senescent cells accumulate in tissues throughout the body with age. Cells constantly become senescent as a result of wound healing, cancer suppression, the Hayflick limit on cellular replication, or damage and a toxic local environment. Near all are destroyed quite quickly, either via programmed cell death or by the immune system. It remains to be rigorously determined as to whether the growth in numbers of senescent cells with age is an imbalance of slowed clearance and increased production, or whether a tiny fraction of all senescent cells manage to evade destruction and linger for the long term.

What is certain is that the burden of senescent cells is very damaging to health. Senescent cells generate the senescence-associated secretory phenotype, a secreted mix of molecules that causes chronic inflammation, destructive remodeling of surrounding tissue, and dysfunction of nearby cells. A comparatively small number of senescent cells can cause meaningful loss of organ function and the onset of age-related disease. This is thus one of the important contributing causes of aging.

The research community is exploring the consequences of cellular senescence tissue by tissue, starting with those most important to age-related mortality. In the heart, cellular senescence produces fibrosis, a disarray of normal tissue maintenance processes that manifests as inappropriate deposition of scar-like collagen structures. It is also connected to the ventricular hypertrophy that leads to heart failure. Targeted removal of senescent cells has been shown to reverse these pathologies in mice, and as a consequence there is considerable interest in further exploration of the biochemistry of senescence in the aging heart.

Cardiomyocyte Senescence and Cellular Communications Within Myocardial Microenvironments

The heart is an organ with high energy demand: mitochondria content in cardiomyocytes is up to 70%. During aging and stress conditions, the metabolic pattern changes in cardiomyocytes, which is critically involved in the regulation of cardiomyocyte dysfunction and senescence. The non-myocytes (endothelial cells, fibroblasts, and immune cells) in the local microenvironment also contribute to the (dys)function/senescence of cardiomyocytes. In turn, the senescent cardiomyocytes modulate the microenvironment to contribute to functional compensatory response or decompensatory remodeling and cardiac dysfunction.

Although cell senescence plays essential roles in wound healing, limiting atherosclerotic plaque size, and preventing infections, the effects of cell senescence can be detrimental or beneficial. The exact roles of senescent cells that contribute to aging and age-related diseases can be named "senescaging". Further studies are still needed to explore the physiological and pathological functions of senescent cardiomyocyte during cardiac development, regeneration, and pathological remodeling, and to elucidate how senescaging contributes to cardiac aging and disease. Specifically, more studies are needed to answer whether cardiomyocyte senescence critically contributes to cardiac aging and the related heart failure with preserved ejection fraction (HFpEF).

Microenvironmental non-myocytes function as central regulators of cardiomyocyte senescence, and metabolism switch is important for the homeostasis and senescence of cardiomyocytes. As thus, an interesting point is whether these non-myocytes affect the metabolic pattern of cardiomyocyte undergoing senescence. Also, studies are needed to explore how metabolism alternations in non-myocytes contribute to cardiomyocyte senescence and cardiac aging. Many studies have been carried out to study the effects of non-myocytes on cardiomyocyte senescence. Some studies also explored the paracrine effects of cardiomyocytes on non-myocytes. However, our knowledge about the effects of senescent cardiomyocytes on microenvironmental non-myocytes is few and further efforts are needed.

An interesting question is whether cardiomyocyte senescence and the myocardial microenvironment could serve as targets for anti-aging drugs such as the popular senolytics. Senolytics were recently reported to repress senescence and inhibit cardiac disease such as myocardial infarction and repress age-related vasomotor dysfunction and atherosclerosis. Further studies are still needed to elucidate how senolytics target cardiomyocyte senescence and local microenvironment, and that whether other anti-aging drugs could repress the senescaging of myocardial microenvironment.

Cellular senescence is important in the progression of aging, and targeted elimination of senescent cells has been shown to reverse the course of many age-related conditions in animal studies. Atherosclerosis is the build up of fatty plaques in blood vessels, narrowing and weakening to the point of eventual rupture. This occurs because macrophage cells become dysfunctional and fail in their task of maintaining these tissues. Some macrophages in atherosclerotic plaques are senescent, and these cells, as well as senescent cells in the endothelial and other tissues of blood vessels, produce an inflammatory environment that encourages futher macrophage dysfunction.

Removal of these senescent cells has been shown to slow the progression of atherosclerosis in animal models. Here, researchers investigate one mechanism by which cellular senescence arises in blood vessel endothelial tissues. They show that interfering in this mechanism can reduce the burden of cellular senescence in blood vessel walls, and thus slow the progression of atherosclerosis.

CD9, a tetraspanin membrane protein, is known to regulate cell adhesion and migration, cancer progression and metastasis, immune and allergic responses, and viral infection. CD9 is upregulated in senescent endothelial cells, neointima hyperplasia, and atherosclerotic plaques. However, its role in cellular senescence and atherosclerosis remains undefined.

We investigated the potential mechanism for CD9-mediated cellular senescence and its role in atherosclerotic plaque formation. CD9 knockdown in senescent human umbilical vein endothelial cells significantly rescued senescence phenotypes, while CD9 upregulation in young cells accelerated senescence. CD9 regulated cellular senescence through a phosphatidylinositide 3 kinase-AKT-mTOR-p53 signal pathway. CD9 expression increased in arterial tissues from humans and rats with age, and in atherosclerotic plaques in humans and mice.

Anti-mouse CD9 antibody noticeably prevented the formation of atherosclerotic lesions in ApoE knockout mice and Ldlr knockout mice. Furthermore, CD9 ablation in ApoE knockout mice decreased atherosclerotic lesions in aorta and aortic sinus. These results suggest that CD9 plays critical roles in endothelial cell senescence and consequently the pathogenesis of atherosclerosis, implying that CD9 is a novel target for prevention and treatment of vascular aging and atherosclerosis.

Link: https://doi.org/10.1038/s41418-020-0537-9

There is considerable evidence for the proposition that older people engage in too little physical activity. Our modern societies of comfort and our engines of transport enable a sedentary lifestyle, to our detriment. The harms done by remaining sedentary are large enough that physical activity begins to look like an effective intervention. It reduces mortality, slows onset of age-related disease, and, as noted here, can reverse the progression of age-related frailty.

Maintaining a healthy lifestyle in older age is associated with a lower level of frailty. However, studies on the association between physical activity (PA) and frailty among older adults show contradictory results. Some studies suggest that regular PA may delay the onset of frailty and reduce its severity, but others found that PA was not associated with a decreased risk for frailty among older adults. Second, most of the longitudinal studies on PA and frailty examine baseline PA only in relation to changes in frailty, and evidence on the association between change in PA and frailty is limited. Additionally, most studies on PA and frailty have been conducted in adults aged 50 to 70 years, and evidence on the longitudinal association between PA and frailty in adults older than 70 years is relatively scarce.

Most previous studies on PA and frailty have focused on physical frailty only, and to date there has been little research into psychological and social frailty. Therefore, the aim of our study was to examine the longitudinal association between frequency of moderate PA and overall, physical, psychological, and social frailty among community-dwelling older adults older than 70 years. Second, we assessed the association between a 12-month change in frequency of moderate PA and frailty.

Participants who undertook moderate PA with a regular frequency at baseline were less frail at 12-month follow-up than participants with a low frequency. Participants who undertook moderate PA with a continued regular frequency were least frail at baseline and at 12-month follow-up. After controlling for baseline frailty and covariates, compared with participants with a continued regular frequency, participants with a decreased frequency were significantly more overall, physically, psychologically, and socially frail at 12-month follow-up. Participants with a continued low frequency were significantly more overall, physically, psychologically, and socially frail at 12-month follow-up. The 12-month follow-up frailty level of participants who undertook moderate PA with an increased frequency was similar to those with a continued regular frequency.

Link: https://doi.org/10.1111/jgs.16391

The amyloid cascade hypothesis is the earliest coherent view of the development of Alzheimer's disease. In this view, the condition begins with the slow aggregation of amyloid-β over many years, and this process sets up the cell dysfunction and chronic inflammation that allows much more harmful later stage of tau aggregation to get underway in earnest. This hypothesis has dominated research and development for many years, and across this period of time, alternative views and approaches to the condition gained little traction and funding.

Therapies based on clearance on amyloid-β took a long time to achieve the goal of reducing amyloid-β levels in humans. This was only demonstrated in the past few years, and, unfortunately, failed to produce meaningful patient benefits. This has led to considerable unrest and rebellion against the consensus in the Alzheimer's research community. There is a great deal of renewed theorizing, and new directions in the development of therapies are finally seeing greater funding and attention.

One important new direction is the clearance of senescent supporting cells from the brain. Animal data strongly suggests that senescent microglia and astrocytes are causing considerable harm in the aging brain, and are particularly important in Alzheimer's disease. One of the early senolytic drugs, dasatinib, can pass the blood-brain barrier to selectively destroy senescent cells in the brain. It has been used to reverse neurodegeneration and neuroinflammation in animal models of Alzheimer's disease. Is it the case that amyloid-β accumulation creates a greater burden of cellular senescence in old age, and once a significant senescent cell population is established, it doesn't much help to remove the amyloid-β? Maybe so.

Senescence as an Amyloid Cascade: The Amyloid Senescence Hypothesis

Due to their postmitotic status, the potential for neurons to undergo senescence has historically received little attention. This lack of attention has extended to some non-postmitotic cells as well. Recently, the study of senescence within the central nervous system (CNS) has begun to emerge as a new etiological framework for neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD).

The presence of senescent cells is known to be deleterious to non-senescent neighboring cells via development of a senescence-associated secretory phenotype (SASP) which includes the release of inflammatory, oxidative, mitogenic, and matrix-degrading factors. Senescence and the SASP have recently been hailed as an alternative to the amyloid cascade hypothesis and the selective killing of senescence cells by senolytic drugs as a substitute for amyloid beta (Aß) targeting antibodies.

Here we call for caution in rejecting the amyloid cascade hypothesis and to the dismissal of Aß antibody intervention at least in early disease stages, as Aß oligomers (AßO), and cellular senescence may be inextricably linked. We will review literature that portrays AßO as a stressor capable of inducing senescence. We will discuss research on the potential role of secondary senescence, a process by which senescent cells induce senescence in neighboring cells, in disease progression. Once this seed of senescent cells is present, the elimination of senescence-inducing stressors like Aß would likely be ineffective in abrogating the spread of senescence. This has potential implications for when and why AßO clearance may or may not be effective as a therapeutic for AD.

The selective killing of senescent cells by the immune system via immune surveillance naturally curtails the SASP and secondary senescence outside the CNS. Immune privilege restricts the access of peripheral immune cells to the brain parenchyma, making the brain a safe harbor for the spread of senescence and the SASP. However, an increasingly leaky blood brain barrier (BBB) compromises immune privilege in aging AD patients, potentially enabling immune infiltration that could have detrimental consequences in later AD stages. Rather than an alternative etiology, senescence itself may constitute an essential component of the cascade in the amyloid cascade hypothesis.

In this interesting open access paper, the authors explore the contribution of changes in the extracellular matrix to the deterioration of muscle function that takes place with aging. The extracellular matrix is produced and maintained by cells, and gives tissue its structural properties. It is a complex arrangement of molecules such as collagen and elastin, continually updated by cells, and not always for the better as aging progresses. Chronic inflammation, for example, provokes excessive and inappropriate deposition of collagen. Further, elastin molecules tend not be replaced at the same pace as they are damaged or broken down. In addition, persistent cross-links form between extracellular matrix molecules, altering structural properties such as elasticity. This is most apparent in skin and blood vessels, but, as the researchers here point out, these are not the only places in the body in which changes in the extracellular matrix are important.

In humans, the stiffness of the muscle-tendon complex in situ increases with aging, and this is mainly attributed to an increase in muscle stiffness, while tendons display greater compliance. Importantly, the age-related increase in stiffness of the muscle-tendon complex has been considered relevant to the preservation of eccentric force in the elderly. Whole muscle stiffness depends on the mechanical properties of muscle fibers and of extracellular matrix (ECM), and it is still debated whether muscle fibers or ECM are the determinants of such change.

To answer this question, we compared the passive stress generated by elongation of fibers alone and arranged in small bundles in young healthy (Y: 21 years) and elderly (E: 67 years) subjects. The physiological range of sarcomere length 2.5-3.3 μm was explored. The area of ECM between muscle fibers was determined on transversal sections with picrosirius red, a staining specific for collagen fibers.

The passive tension of fiber bundles was significantly higher in E compared to Y at all sarcomere lengths. However, the resistance to elongation of fibers alone was not different between the two groups, while the ECM contribution was significantly increased in E compared to Y. The proportion of muscle area occupied by ECM increased from 3.3% in Y to 8.2% in E. When the contribution of ECM to bundle tension was normalized to the fraction of area occupied by ECM, the difference disappeared. We conclude that, in human skeletal muscles, the age-related reduced compliance is due to an increased stiffness of ECM, mainly caused by collagen accumulation.

Link: https://doi.org/10.3390/ijms21113992

Retrotransposons are receiving more attention in the context of aging these days. They are the remnants of ancient viruses, capable of copying themselves around the genome. The mechanisms repressing this copying tend to fail with age, and retrotransposons become a potential source of DNA damage and metabolic disarray. They are not the only class of repetitive elements in the genome, however. Here, researchers discuss the broader category of repetitive elements and their increasing presence with advancing age. Assessing repetitive element activity, such as by looking for them in the transcriptome, may be a potential biomarker of biological age.

One particularly large and often-ignored fraction of the human genome (more than 60%) is composed of repetitive elements (RE). These include: types 1 and 2 transposons (retrotransposons and DNA transposons, respectively), some of which can self-copy and reinsert into new locations; terminal repeats at the ends of retrotransposons; and tandem repeats, including sequences common to centromeres, chromatin, and other structured genome regions. Most RE are chromatinized and suppressed, but certain retrotransposons remain active in humans and may be involved in aging. Indeed, studies in mice and other model organisms have shown that active/transposable RE, in particular, contribute to the aging process, although most evidence points to RE activation later in life (e.g., in senescence).

The potential for RE in general to serve as a transcriptomic marker of aging has not been investigated, especially in humans, but we and others have reported a generic accumulation of RE transcripts (i.e., not only active RE) in age-related neurodegenerative processes and diseases. Evidence also indicates that chromatin maintenance declines with aging, which could increase general transcriptional accessibility of RE. As such, age-related changes in global RE transcript levels could be a good transcriptomic/mechanistic marker of aging.

Here, we used multiple RNA-seq datasets generated from human samples and Caenorhabditis elegans and found that most RE transcripts (a) accumulate progressively with aging; (b) can be used to accurately predict age; and (c) may be a good marker of biological age. The strong RE/aging correlations we observed are consistent with growing evidence that RE transcripts contribute directly to aging and disease.

Link: https://doi.org/10.1111/acel.13167

Senolytic therapies are those that selectively destroy senescent cells. Cells that become senescent grow in size, cease to replicate, and generate a potent mix of molecules known as the senescence-associated secretory phenotype (SASP). Senescence occurs at the Hayflick limit on cellular replication, or in response to cell damage and a toxic local environment. The SASP provokes the immune system into an inflammatory state, disrupts tissue structure and function, and encourages nearby cells to also become senescent. It is useful in the short term, in the context of wound healing and cancer suppression for example, but when present for the long-term, the SASP is an important cause of degenerative aging. A significant fraction of aging and age-related disease is driven by the accumulation of senescent cells throughout the body, and hence the research community is quite interested in finding ways to get rid of these errant cells.

The earliest discovered senolytic small molecule drugs are chemotherapeutics. It is fair to say that they are selective for senescent cells, but in some cases far from selective enough. They kill a lot of non-senescent cells and, further, cause all sorts of problematic and potentially serious side-effects. In addition, drugs such as the small molecules targeting Bcl-2 family proteins, particularly navitoclax, tend to require a few weeks of dosing at chemotherapeutic levels to generate senolytic effects. This is as opposed to the few doses or intermittent doses of the arguably more effective senolytic chemotherapeutic dasatinib. Less of a chemotherapeutic drug is almost always a good thing.

The open access paper I'll point out today provides an additional incentive to avoid navitoclax as a senolytic treatment. It does indeed kill senescent cells in aged tissues, but it is just too toxic, with too many harmful side-effects, for use in the clinic. This is the case, at least, without the use of one or more of the clever adaptations to limit its harms that have been proposed of late. Whether or not these approaches make it into clinical use is somewhat hit and miss, however, given that there are many other alternative senolytic therapies presently under development.

The Senolytic Drug Navitoclax (ABT-263) Causes Trabecular Bone Loss and Impaired Osteoprogenitor Function in Aged Mice

Senescence is a cellular defense mechanism that helps cells prevent acquired damage, but chronic senescence, as in aging, can contribute to the development of age-related tissue dysfunction and disease. Previous studies clearly show that removal of senescent cells can help prevent tissue dysfunction and extend healthspan during aging. Senescence increases with age in the skeletal system, and selective depletion of senescent cells or inhibition of their senescence-associated secretory phenotype (SASP) has been reported to maintain or improve bone mass in aged mice.

This suggests that promoting the selective removal of senescent cells, via the use of senolytic agents, can be beneficial in the treatment of aging-related bone loss and osteoporosis. Navitoclax (also known as ABT-263) is a chemotherapeutic drug reported to effectively clear senescent hematopoietic stem cells, muscle stem cells, and mesenchymal stromal cells in previous studies, but its in vivo effects on bone mass had not yet been reported. Therefore, the purpose of this study was to assess the effects of short-term navitoclax treatment on bone mass and osteoprogenitor function in old mice.

Aged (24 month old) male and female mice were treated with navitoclax (50 mg/kg body mass daily) for 2 weeks. Surprisingly, despite decreasing senescent cell burden, navitoclax treatment decreased trabecular bone volume fraction in aged female and male mice (-60.1% females, -45.6% males), and bone marrow stromal cells (BMSC) derived osteoblasts from the navitoclax treated mice were impaired in their ability to produce a mineralized matrix (-88% females, -83% males). Moreover, in vitro administration of navitoclax decreased BMSC colony formation and calcified matrix production by aged BMSC-derived osteoblasts, similar to effects seen with the primary BMSC from the animals treated in vivo. Navitoclax also significantly increased metrics of cytotoxicity in both male and female osteogenic cultures.

Taken together, these results suggest a potentially harmful effect of navitoclax on skeletal-lineage cells that should be explored further to definitively assess navitoclax's potential (or risk) as a therapeutic agent for combating age-related musculoskeletal dysfunction and bone loss.

Chronically raised blood pressure, or hypertension, is highly damaging to tissues throughout the body. It is an important mechanism linking the molecular damage of aging to gross structural damage to organs, causing loss of function, age-related disease, and death. Many of the underlying causes of aging lead to stiffness of blood vessel walls, from cross-linking in the extracellular matrix to the effects of senescent cell signaling on vascular smooth muscle cells. That stiffness causes dysfunction in the regulation of blood pressure, which in turn causes pressure damage, increased pace of the development of atherosclerosis, and other age-related issues.

Taking blood pressure medication as prescribed helped even the frailest elderly people (65 and older) live longer, and the healthiest older people had the biggest survival boost, according to a large study in northern Italy. Researchers reviewed data on almost 1.3 million people aged 65 and older (average age 76) in the Lombardy region of northern Italy who had three or more high blood pressure medication prescriptions in 2011-2012. Examining the public health care database, researchers calculated the percentage of time over the next seven years (or until death) that each person continued to receive the medications. Because almost all medications are free or low-cost and dispensed by the public health service, this corresponds roughly to people's adherence in using the medication in Italy.

Researchers compared roughly 255,000 people who died during the 7-year follow-up with age-, gender-, and health-status-matched controls who survived and divided them into four groups of health status: good, medium, poor, or very poor. The probability of death over 7-years was 16% for people rated in good health at the beginning of the study. Mortality probability increased progressively to 64% for those rated in very poor health.

Compared with people with very low adherence to blood pressure medications, meaning dispensed pills covered less than 25% of the time period, people with high adherence to blood pressure medications, meaning more than 75% of the time period covered, were: (a) 44% less likely to die if they started in good health; and (b) 33% less likely to die if they started in very poor health. A similar pattern was seen with cardiovascular deaths. The greatest survival benefit was among the people who started in good health, and the most modest survival benefit was in those who started in very poor health. "Our findings definitely suggest that even in very frail people, antihypertensive treatment reduces the risk of death; however, the benefits may be smaller in this group."

Link: https://newsroom.heart.org/news/blood-pressure-medications-help-even-the-frailest-elderly-people-live-longer

This interesting study suggests that it may be possible to turn off many forms of autoimmunity by inducing tolerance, in a comparatively simple manner, to the specific fragment of a protein that is causing an immune reaction. There are autoimmunities in which the specific trigger is poorly understood, including the only vaguely cataloged and no doubt highly variable autoimmunities of aging, but many other conditions for which this might be a useful approach.

Autoimmune diseases are caused when the immune system loses its normal focus on fighting infections or disease within and instead begins to attack otherwise healthy cells within the body. In the case of multiple sclerosis (MS), the body attacks proteins in myelin - the fatty insulation-like tissue wrapped around nerves - which causes the nerves to lose control over muscles.

Scientists examined the intricate mechanisms of the T-cells that control the body's immune system and found that the cells could be 're-trained' to stop them attacking the body's own cells. In the case of multiple sclerosis, this would prevent the body from attacking the Myelin Basic Protein (MBP) by reprogramming the immune system to recognise the protein as part of itself.

The first stage showed that the immune system can be tricked into recognising MBP by presenting it with repeated doses of a highly soluble fragment of the protein that the white blood cells respond to. By repeatedly injecting the same fragment of MBP, the process whereby the immune system learns to distinguish between the body's own proteins and those that are foreign can be mimicked. The process, which is a similar type of immunotherapy to that previously used to desensitise people against allergies, showed that the white blood cells that recognise MBP switched from attacking the proteins to actually protecting the body.

The second stage, saw gene regulation specialists probe deep within the white blood cells that react to MBP to show how genes are rewired in response to this form of immunotherapy to fundamentally reprogram the immune system. The repeated exposure to the same protein fragment triggered a response that turns on genes that silence the immune system instead of activating it. These cells then had a memory of this exposure to MBP embedded in the genes to stop them setting off an immune response. When T cells are made tolerant, other genes which function to activate the immune system remain silent.

Link: https://www.eurekalert.org/pub_releases/2020-06/uob-bs060920.php

The search for viable biomarkers of aging is an active field of research. The ability to rapidly and cheaply assess biological age, the burden of cell and tissue damage and dysfunction that causes disease and mortality, would greatly speed the development of rejuvenation therapies. At present it is costly and slow to demonstrate that any given approach to rejuvenation actually works: one needs to run a life span study, which is prohibitively expensive in mice and simply impractical in humans. What is needed is a test that can be carried out immediately before and immediately after an intervention, and which accurately assesses the state of aging.

Numerous approaches to a biomarker of aging have been suggested, or are at various stages of development. Aging clocks based on selected epigenetic markers, protein levels, or portions of the transcriptome are all popular approaches. Weighted algorithmic combinations of simple metrics such as grip strength and walking speed have also been explored. Other approaches exist. For example, in today's research materials, scientists suggest that assessment of molecular changes in the lens of the eye is worthy of consideration.

The challenge with all of these biomarkers of biological age is that it is very unclear as to how they connect specifically to the underlying causes of aging. It isn't unreasonable to think that some biomarkers reflect only certain forms of the cell and tissue damage of aging, or certain downstream consequences rather than all of them. Which is fine if only looking and not intervening. But this means that one can't just run an assessment of a specific approach to rejuvenation coupled with a specific biomarker, and have any great confidence that the numbers will be meaningful at the end of the study. At the present time, any biomarker used must be calibrated against a specific rejuvenation therapy in order to determine how it responds. This rather defeats the point of the exercise, as that calibration is going to require numerous life span studies.

Eye scanner detects molecular aging in humans

All people age, but individuals do so at different rates, some faster and others slower. While this observation is common knowledge, there is no universally accepted measure of biological aging. Numerous aging-related metrics have been proposed and tested, but no marker to date has been identified or noninvasive method developed that can accurately measure and track biological aging in individuals. In what is believed to be the first study of its kind, researchers have discovered that a specialized eye scanner that accurately measures spectroscopic signals from proteins in lens of the eye can detect and track biological aging in living humans.

"The lens contains proteins that accumulate aging-related changes throughout life. These lens proteins provide a permanent record of each person's life history of aging. Our eye scanner can decode this record of how a person is aging at the molecular level. Eye scanning technology that probes lens protein affords a rapid, noninvasive, objective technique for direct measurement of molecular aging that can be easily, quickly, and safely implemented at the point of care. Such a metric affords potential for precision medical care across the lifespan."

In Vivo Quasi-Elastic Light Scattering Eye Scanner Detects Molecular Aging in Humans

The absence of clinical tools to evaluate individual variation in the pace of aging represents a major impediment to understanding aging and maximizing health throughout life. The human lens is an ideal tissue for quantitative assessment of molecular aging in vivo. Long-lived proteins in lens fiber cells are expressed during fetal life, do not undergo turnover, accumulate molecular alterations throughout life, and are optically accessible in vivo.

We used quasi-elastic light scattering (QLS) to measure age-dependent signals in lenses of healthy human subjects. Age-dependent QLS signal changes detected in vivo recapitulated time-dependent changes in hydrodynamic radius, protein polydispersity, and supramolecular order of human lens proteins during long-term incubation (~1 year) and in response to sustained oxidation (~2.5 months) in vitro. Our findings demonstrate that QLS analysis of human lens proteins provides a practical technique for noninvasive assessment of molecular aging in vivo.

Calorie restriction, eating up to 40% fewer calories while maintaining optimal micronutrient intake, improves health and reliably extends life in most species. In humans it produces robust improvements in health, but we experience a much lesser degree of life extension than short-lived species such as mice. Calorie restriction research has given rise to a number of lines of work in which specific dietary components (such as individual essential amino acids) are restricted, to try to identify which of these components are responsible for the benefits. A sizable fraction of the calorie restriction response is thought to be triggered by low dietary intake of the essential amino acid methionine, for example. In contrast to that body of work, researchers here restrict threonine, another essential amino acid, in laboratory mice, and observe an interesting set of benefits.

The current classification of essential amino acids (EAA) is based on the nutritional requirements for growth and vitality under nil dietary supply of an amino acid. However, humans rarely face dramatic protein/amino acid insufficiency, and for the first time in human history, nutritional excesses mean the amount of overweight people outnumber the amount of underweight people on a global scale. This calls for a reconsideration of amino acid functions in nutrition, now based upon health-related criteria.

One approach is dietary protein dilution (DPD), where protein is reduced and replaced by other nutrient sources, and is distinct from caloric restriction. Unlike severe protein/amino acid restriction, which is not compatible with vitality, moderate DPD promotes longevity in multiple species including flies, rodents, and perhaps humans. Furthermore, DPD also affects health-span and preclinical studies have demonstrated that DPD can retard age-related diseases such as cancer, type 2 diabetes, and dyslipidemia/fatty liver disease. Notably, dietary protein intake rates are positively related to type 2 diabetes risk as well as all-cause mortality in humans.

Here, by mimicking amino acid supply from a casein-based diet, we demonstrate that restriction of dietary EAA, but not non-EAA, drives the systemic metabolic response to total amino acid deprivation; independent from dietary carbohydrate supply. Furthermore, systemic deprivation of threonine and tryptophan, independent of total amino acid supply, are both adequate and necessary to confer the systemic metabolic response to amino acid restriction.

Dietary threonine restriction (DTR) retards the development of obesity-associated metabolic dysfunction. Liver-derived fibroblast growth factor 21 is required for the metabolic remodelling with DTR. Strikingly, hepatocyte-selective establishment of threonine biosynthetic capacity reverses the systemic metabolic response to DTR. Taken together, our studies of mice demonstrate that the restriction of EAA are sufficient and necessary to confer the systemic metabolic effects of DPD.

Link: https://doi.org/10.1038/s41467-020-16568-z

Kidney function is critical to health, but, as is the case for all organs, the kidneys declines with age. The damage of aging produces harmful outcomes in many ways. For example, hypertension causes structural pressure damage in sensitive tissues in the kidneys. Further, senescent cells and other sources of chronic inflammation disrupt normal tissue maintenance processes in the kidneys, leading to the scar-like collagen deposits of fibrosis. In turn, loss of kidney function accelerates many other aspects of aging, including neurodegeneration and the onset of cognitive decline.

An international study that has been carried out on nearly 3000 people in Norway, Germany, and Iceland, shows that our kidney function deteriorates with age, even if we do not have any other diseases. One of the groups that have participated in the study consists of over 1600 people and stems from the Tromsø Study, which is Norway's most comprehensive and best participated population study throughout 40 years. This group has been through the different examinations three times; between 2007 to 2009, 2013 to 2015, and 2018 to 2020.

"What we see is that what happens in our kidneys when we age is representative of all the other things that happen in our bodies. The kidney function deteriorates, not because we get ill, but as part of ageing. Loss of kidney function is something that happens to all humans and is thus a way to determine ageing in general. There is still variation as to how quickly this happens, and we still do not have good answers as to why this variation occurs. We have examined many factors that can play a part as to why some of us experience larger loss of kidney function than others."

The researchers use a precise method of measuring kidney function. They inject a substance into the blood veins that only separates into the kidneys, and let a few hours pass before they measure how much of the substance remains in the blood. This gives a measure of the kidney's ability to remove toxins and waste products. Researchers explain that more people may experience loss of kidney function as it becomes more common to survive diseases like cancer and heart and vascular diseases.

Link: https://www.eurekalert.org/pub_releases/2020-06/utau-kdw060820.php

Mitochondrial uncoupling is the mechanism by which cells generate heat. Mitochondria are the power plants of the cell, a herd of bacteria-like structures that conduct energetic processes to generate the chemical energy store molecule adenosine triphosphate (ATP). ATP is used to power all of the vital biochemical machinery of a cell. Mitochondrial uncoupling is a regulatory mechanism that changes the operation of a mitochondrion such that the energy it accumulates is dissipated as heat rather than powering the chemical reactions needed to generate ATP. This uncoupling is how mammals regulate body temperature.

Raised levels of mitochondrial uncoupling can produce useful outcomes to health over the long term. It can be protective of tissues by reducing the degree to which mitochondria generate oxidative molecules. Unfortunately, this class of intervention so far doesn't appear to increase life span, despite tending to reduce excess visceral fat tissue, a significant contributing cause of age-related disease. The practice of calorie restriction does increase mitochondrial uncoupling, but it is unclear as to the degree to which this is important to the outcome of improved health and longevity that occurs in calorie restricted animals.

Nonetheless, there has been some effort over the years to produce drugs that can increase mitochondrial uncoupling. The primary objection to the use of such compounds in the clinic is that, historically, they have not been all that safe. They increase uncoupling in a dose-dependent manner, but increasing uncoupling to a sizable degree can result in severe trauma or death due to excess heat generation. The distance between a useful dose and a lethal dose just isn't large enough for comfort. DNP is a good example of such a compound, one with the added safety concern of being explosive. There are signs of progress, however. Researchers here report on a mitochondrial uncoupling drug candidate that appears to be useful at reasonable doses and, more importantly, safe at high doses.

Drug researcher develops 'fat burning' molecule that has implications for treatment of obesity

Researchers have recently identified a small mitochondrial uncoupler, named BAM15, that decreases the body fat mass of mice without affecting food intake and muscle mass or increasing body temperature. Additionally, the molecule decreases insulin resistance and has beneficial effects on oxidative stress and inflammation. The findings hold promise for future treatment and prevention of obesity, diabetes, and especially nonalcoholic steatohepatitis (NASH), a type of fatty liver disease that is characterized by inflammation and fat accumulation in the liver.

The mitochondria are commonly referred to as the powerhouses of the cell. The organelle generates ATP, a molecule that serves as the energy currency of the cell, which powers body movement and other biological processes that help our body to function properly. In order to make ATP, nutrients need to be burned and a proton motive force (PMF) needs to be established within the mitochondria. The PMF is generated from a proton gradient, where there is a higher concentration of protons outside of the inner membrane and a lower concentration of protons in the matrix, or the space within the inner membrane. The cell creates ATP whenever protons pass through an enzyme called ATP synthase, which is embedded in the membrane. Hence, nutrient oxidation, or nutrient burning, is coupled to ATP synthesis. Mitochondrial uncouplers transport protons into the matrix by bypassing ATP synthase, which throws off the PMF. To reestablish the gradient, protons must be exported out of the mitochondrial matrix. As a result, the cell begins to burn fuel at higher than necessary levels.

Knowing that these molecules can change a cell's metabolism, researchers wanted to be sure that the drug was reaching its desired targets and that it was, above all, safe. Through a series of mouse studies, the researchers found that BAM15 is neither toxic, even at high doses, nor does it affect the satiety center in the brain, which tells our body if we are hungry or full. Another side effect of previous mitochondrial uncouplers was increased body temperature. Researchers measured the body temperature of mice who were fed BAM15. They found no change in body temperature. In the BAM15 mouse studies, animals ate the same amount as the control group - and they still lost fat mass.

Mitochondrial uncoupler BAM15 reverses diet-induced obesity and insulin resistance in mice

Obesity is a health problem affecting more than 40% of US adults and 13% of the global population. Anti-obesity treatments including diet, exercise, surgery and pharmacotherapies have so far failed to reverse obesity incidence. Herein, we target obesity with a pharmacotherapeutic approach that decreases caloric efficiency by mitochondrial uncoupling. We show that a recently identified mitochondrial uncoupler BAM15 is orally bioavailable, increases nutrient oxidation, and decreases body fat mass without altering food intake, lean body mass, body temperature, or biochemical and haematological markers of toxicity.

BAM15 decreases hepatic fat, decreases inflammatory lipids, and has strong antioxidant effects. Hyperinsulinemic-euglycemic clamp studies show that BAM15 improves insulin sensitivity in multiple tissue types. Collectively, these data demonstrate that pharmacologic mitochondrial uncoupling with BAM15 has powerful anti-obesity and insulin sensitizing effects without compromising lean mass or affecting food intake.

Many aspects of aging correlate with one another, even those with quite different underlying mechanisms and proximate causes. The various forms of root cause damage that result in the aging process, as well as their downstream consequences, all interact with one another. So whether or not any specific correlation teaches us anything about the way in which aging works under the hood is very dependent on the details. That loss of vision and hearing correlate with dementia risk is known, but the relative contribution of different mechanisms is up for debate. How much is due to similar biochemical mechanisms of damage in nervous system tissues, and how much is due to loss of sensory stimulation, for example.

Recent studies reported that the incidence of dementia in western countries may be declining whereas low and middle income countries are predicted to have the largest increase in incident dementia. This discrepancy is suggested to be due to the differences in the effective management of cardiovascular disease, hypertension, and diabetes in these regions. However, even though early recognition of risk factors for dementia is of utmost priority, the sporadic incidence of dementia is a challenge in preventive medicine.

Previous studies have suggested that an association exists between vision loss and cognitive impairment. Low vision and blindness are commonly seen in the older population as the risk of developing cataract; age-related macular degeneration and glaucoma increase with advancing age. Despite the body of evidence, there are few reports regarding causal relationships or direct association between low vision and dementia. A clear understanding of this association may facilitate the development of strategies for reducing the burden of cognitive impairment.

The National Health Insurance Service (NHIS) database has recently become accessible to researchers in Korea. This large-scale database permits the identification of the longitudinal incidence of diseases and allows for the analysis of the association between diseases and health conditions. Using the six levels of disability of the Korean rating system, an individual with low vision can be classified depending on his/her visual acuity. Employing the disability grade used in Korea, we were able to investigate the impact of low vision on incident dementia by using a nationwide population-based cohort that includes over 1.5 million Koreans.

Statistical analysis showed that subjects with more severe visual impairments have a higher risk of dementia, Alzheimer's disease, and vascular dementia after adjusting for compounding variables. The hazard ratios (HRs) of dementia increased significantly as visual acuity worsened: 1.444 for visual acuity (VA) < 1.0, 1.734 for VA < 0.3, 1.727 for VA < 0.1, and 1.991 for visual loss. Baseline visual loss and visual impairment were positively associated with the risk of dementia, Alzheimer's disease, and vascular dementia. From the results of this nationwide population-based cohort study, we suggest that there is a significant increase in the incidence of dementia in subjects with low vision.

Link: https://doi.org/10.1038/s41598-020-66002-z

As noted here, the circulation of blood through the brain slows in specific ways with increasing age. Taken as a biomarker, this correlates with one of the noteworthy structural changes that take place in the aging brain, the enlargement of the ventricles that results from slowed fluid drainage. This is perhaps worth comparing with the work of recent years on the impaired drainage of cerebrospinal fluid in the aging of the brain, though this is more a matter of failing to remove molecular waste rather than fluid dynamics issues leading to damage to tissue structure. Another line of research to consider is the loss of capillary density in tissues with age, as perhaps this is an important mechanism involved in an age-related slowing of the passage of blood through brain tissue.

Ventriculomegaly is an abnormal condition in which fluid accumulates in the ventricles of the brain without properly draining, making them enlarged. Although ventricular enlargement within normal range is not itself considered a disease, when left unchecked it can lead to ventriculomegaly and dementia resulting from normal pressure hydrocephalus. In their study, the team found that ventriculomegaly was associated with changes in blood circulation of the brain.

After blood circulates through the brain providing necessary oxygen, the deoxygenated blood must return to the heart though our veins. This happens through two pathways, one draining blood from regions close to the surface of the brain, and the other from areas deep in the brain. By using MRI to measure changes in blood flow, the team recently found that as we age, the time it takes for blood to drain through these two pathways becomes out of sync. The result is a time lag between the deep drainage pathway and the surface pathway, which increases with age.

In the new study, the researchers found that in healthy aging, the time lag in circulation grows at almost the same rate as enlarging ventricles, but begins slightly earlier. A diagnostic MRI that measures an individual's lag between the two drainage pathways might be a good biomarker for the aging brain, and a possible predictor of ventriculomegaly. Because dementia resulting from hydrocephalus can be reversed by removing the fluid that builds up in the ventricles, early diagnosis is critical.

Link: https://www.riken.jp/en/news_pubs/research_news/pr/2020/20200515_1/index.html

The formation of stress granules in cells is an interesting topic. As the name might suggest, this behavior emerges in cells undergoing stress, such as lack of nutrients, heat, cold, and so forth. Stress granules are transient structures that form within cells, made up of a wide variety of biomolecules that are packed away in a complex manner. These structures may act as a repository for useful molecules, protecting them from aggressive recycling processes triggered by cellular stress, but their function is much debated and comparatively poorly understood.

Mild cellular stress exerts a beneficial hormetic effect, improving health and longevity by triggering greater activity of cellular maintenance processes such as autophagy. Autophagy acts to recycle damaged and unwanted cellular machinery, breaking down proteins, structures, and molecular waste. Calorie restriction is one of the better studied ways to induce mild stress, stress responses, and consequent extension of life in short-lived species. Researchers have demonstrated that upregulation of autophagy is key to that outcome.

In today's open access paper, the authors report that the formation of stress granules is also essential to extension of life via calorie restriction, at least in nematode worms. It reinforces the concept of stress granules as a necessary part of the overall response to stress, a protective mechanism that prevents vital molecular machinery from being broken down by increased recycling.

AMPK-mediated formation of stress granules is required for dietary restriction-induced longevity in Caenorhabditis elegans

Regulation of cellular homeostasis is pivotal for the survival of a cell. Highly conserved mechanisms have evolved which enable cells to cope with various environmental stresses that often disrupt cellular homeostasis. Sequestration of nontranslating mRNAs into stress granules (SGs) is one such mechanism that attenuates protein synthesis during stress. Stress granules are cytosolic assemblies consisting of nontranslating mRNAs, small 40S ribosomes, mRNA-associated translation initiation complexes, and RNA-binding proteins.

It has been suggested that the SGs function as triage sites redirecting mRNAs to either translation, sequestration, or degradation. Therefore, SG assembly represents a key role in protein and RNA homeostasis under adverse conditions and is a tightly regulated process. Not surprisingly, dysregulation of SG dynamic has recently been linked to various diseases, such as cancer, inflammatory, neurodegenerative, and neuromuscular diseases.

It has been previously demonstrated that SG formation enhances cell survival and stress resistance. However, the physiological role of SGs in organismal aging and longevity regulation remains unclear. In this study, we used markers to monitor the formation of SGs in Caenorhabditis elegans. We found that, in addition to acute heat stress, SG formation could also be triggered by dietary changes, such as starvation and dietary restriction (DR). We found that HSF-1 is required for the SG formation in response to acute heat shock and starvation but not DR, whereas the AMPK-eEF2K signaling is required for starvation and DR-induced SG formation but not heat shock. Moreover, our data suggest that this AMPK-eEF2K pathway-mediated SG formation is required for lifespan extension by DR, but dispensable for the longevity by reduced insulin/IGF-1 signaling.

The cellular organelles known as lysosomes are packed full of enzymes, enabling the recycling of metabolic waste and damaged or unwanted proteins and structures by breaking them down into their component parts. Lysosomes are a vital part of the mechanisms of autophagy, working to keep cells from being overtaken by damaged and dysfunctional components. Unfortunately, lysosomal function declines with age, particularly in long-lived cells of the nervous system. Not all metabolic waste is easily broken down, and lysosomes become bloated with a mix of compounds known as lipofuscin. This degrades their performance, and cells suffer accordingly. Lysosomal function is so critical to cell and tissue function that it isn't surprising to see that mutant lineages of laboratory species that exhibit slowed aging also exhibit better, more functional lysosomes.

One of the most universal hallmarks of aging is the decline in protein homeostasis. Studies in a variety of organisms have uncovered age-dependent accumulation of misfolded and damaged proteins, which may impair cell function and homeostasis, leading to the development of age-related diseases. Misfolded, aggregated and damaged proteins can be removed by the proteasome or cleared through the autophagy-lysosome pathway. As the key organelle for cellular degradation, lysosomes exhibit age-related changes. In order to understand whether and how lysosomes alter with age and contribute to lifespan regulation, we characterized multiple properties of lysosomes during the aging process in C. elegans.

We uncovered age-dependent alterations in lysosomal morphology, motility, acidity, and degradation activity, all of which indicate a decline in lysosome function with age. The age-associated lysosomal changes are suppressed in the long-lived mutants daf-2, eat-2, and isp-1, which extend lifespan by inhibiting insulin/IGF-1 signaling, reducing food intake and impairing mitochondrial function, respectively. We found that 43 lysosome genes exhibit reduced expression with age, including genes encoding subunits of the proton pump V-ATPase and cathepsin proteases. The expression of lysosome genes is upregulated in the long-lived mutants, and this upregulation requires the functions of DAF-16/FOXO and SKN-1/NRF2 transcription factors. Impairing lysosome function affects clearance of aggregate-prone proteins and disrupts lifespan extension in daf-2, eat-2, and isp-1 worms.

Our data indicate that lysosome function is modulated by multiple longevity pathways and is important for lifespan extension. Further studies are required to understand whether lysosomes make tissue-specific contributions to aging and lifespan extension.

Link: https://doi.org/10.7554/eLife.55745

The open access paper here makes an interesting companion piece to a recent review of what is known of the role of fat tissue in the longevity of dwarf mouse lineages with disrupted growth hormone signaling. The loss of function in mice is analogous to that found in the small human population that exhibits Laron syndrome. Examination of that population has not yet produce unarguable evidence of any greater life span or resistance to age-related disease. From the evidence to date, we should probably expect favorable adjustments in longevity related to growth hormone and insulin signaling to fall into the broad class of interventions that have much larger effects in short-lived species, such as mice, than in long-lived species, such as our own.

Long-lived mutant mice, such as Ames dwarf, Snell dwarf, and GKO mice, have increased percent body fat and abnormal fat distribution, with preservation of subcutaneous and relatively less visceral fat compared to controls, raising the idea that altered function of adipose tissue within these mice may contribute to their insulin sensitivity, longevity, and disease resistance. To delineate the effects of GH on specific tissues, we evaluated adipose tissue in mice with global disruption of GHR (GKO mice), as well as mice with disruption of GHR in liver (LKO), muscle (MKO), or fat (FKO).

Based on the structure and function of adipocytes and their surrounding stroma, adipose tissue is divided into two categories, white adipose tissue (WAT) and brown adipose tissue (BAT). Its function is to store excess energy in the form of triglycerides for future use. BAT is responsible for dissipating energy in the form of heat through non-shivering thermogenesis. Adipose tissue also influences the activity of macrophages, T cells, B cells, mast cells, dendritic cells, and neutrophils. The inflammatory response of adipose tissue is mainly regulated by macrophages. M1 macrophages produce pro-inflammatory cytokines. In contrast, M2 macrophages are anti-inflammatory and help to maintain tissue homeostasis. In principle, delay or reversal of M1/M2 macrophage polarization might contribute to the insulin sensitivity, disease resistance, and longevity of Ames, Snell, or GKO mice, but no data on this point are yet available.

We report here that white (WAT) and brown (BAT) fat have elevated UCP1 in both kinds of mice, and that adipocytes in WAT depots turn beige/brown. These imply increased thermogenesis and are expected to lead to improved glucose control. Both kinds of long-lived mice show lower levels of inflammatory M1 macrophages and higher levels of anti-inflammatory M2 macrophages in BAT and WAT, with correspondingly lower levels of inflammatory cytokines. Experiments with mice with tissue-specific disruption of GHR showed that these adipocyte and macrophage changes were not due to hepatic IGF1 production nor to direct growth hormone (GH) effects on adipocytes, but instead reflect GH effects on muscle. Muscles deprived of GH signals, either globally (GKO) or in muscle only (MKO), produce higher levels of circulating irisin and its precursor FNDC5. The data thus suggest that the changes in adipose tissue differentiation and inflammatory status seen in long-lived mutant mice reflect interruption of GH-dependent irisin inhibition, with consequential effects on metabolism and thermogenesis.

Link: https://doi.org/10.18632/aging.103380

Senescent cells accumulate throughout the body with age. They are constantly created and destroyed throughout life, but the balance between creation and destruction is upset with age, leading to an accumulated burden of cellular senescence. These cells secrete a potent mix of signals that produce chronic inflammation, disrupt tissue structure and cell function, and encourage other cells to also become senescent. The more senescent cells, the worse the impact. They are an important contributing cause of aging.

Targeted removal of senescent cells has been shown to meaningfully reverse the progression of age-related disease for numerous conditions in animal studies. Further, it extends life span in mice. These results are generally easily replicated and quite robust; we should take it as well settled that clearance of senescent cells in mammals produces literal rejuvenation. Even so, some researchers have suggested that senescence in old tissues might be in some way adaptive, preserving cells that would otherwise not be replaced. Perhaps the balance of negative impacts favors their retention rather than destruction, even though these cells cause harm in their senescent state. This argument has been put forward for senescent T cells of the adaptive immune system, for example, given that new T cells are barely created at all in late life, and even though there are plenty of concrete examples of senescent T cells causing harm.

The proposition of cellular senescence being, on balance, better than the alternative of losing the cells in question entirely cannot be universally (or even broadly) true throughout the body, given the existing animal data on clearance, but perhaps it is true for smaller populations of senescent cells in specific tissues. In the paper I'll point out today, researchers suggest that a class of liver endothelial cells are one such population. This must still be balanced with the greater weight of research suggesting that global clearance of senescent cells is unambiguously beneficial, but as noted here, there are questions as to just how global that global clearance is for various approaches. Populations that are beneficial may be skipped by one or another type of therapy, a situation that could lead to roadblocks in the development of therapies down the line. We shall see.

Defined p16High Senescent Cell Types Are Indispensable for Mouse Healthspan

Substantial evidence has demonstrated that the accumulation of senescent cells can drive many age-associated phenotypes and pathologies. For example, senescent cells accumulate in adipose tissue of patients with diabetes and age-related metabolic dysfunction, in osteoarthritic joints, in the aorta in vascular hyporeactivity and atherosclerosis, and in the lungs in idiopathic pulmonary fibrosis. While selective elimination of these senescent cells confers notable benefits in some tissues, recent studies have also described beneficial roles for senescent cells, raising the question of the differential roles of these cells in various tissues.

Senescence-ablator mouse models have pioneered the field of in vivo senescence studies. With the use of one such model, known as the INK-ATTAC mouse, that is based on a 2,617 base pair fragment of the p16Ink4a gene promoter, it has been proposed that removal of p16-expressing cells results in life extension in mice. The concern, however, is whether the reporter construct with a part of the p16 genomic sequence fully resembles endogenous p16 gene expression, especially with aging. This is further supported by the fact that some p16-expressing cells are not efficiently removed by the INK-ATTAC system in several tissues, including the liver, colon, and T lymphocytes. Thus, it is unclear whether there are important senescent cell types in tissues where the INK-ATTAC system does not work and what impact their removal has on health span.

Here, we generated two knock-in mouse models targeting the best-characterized marker of senescence, p16Ink4a. Using a genetic lineage tracing approach, we found that age-induced p16High senescence is a slow process that manifests around 10-12 months of age. The majority of p16High cells were vascular endothelial cells mostly in liver sinusoids (LSECs), and to lesser extent macrophages and adipocytes. In turn, continuous or acute elimination of p16High senescent cells disrupted blood-tissue barriers with subsequent liver and perivascular tissue fibrosis and health deterioration. Our data show that senescent LSECs are not replaced after removal and have important structural and functional roles in the aging organism. In turn, delaying senescence or replacement of senescent LSECs could represent a powerful tool in slowing down aging.

A great many research groups are engaged in the search for distinct biochemistry in extremely old humans. How do older individuals survive where their peers did not, and can any of the answer to that question be turned into useful therapies? My suspicion is that there are no useful therapies to be found in the genetics and metabolism of exceptional human longevity: these people are still suffering a high burden of damage, and are greatly diminished in capacity. The differences they carry do not tend to swing the odds far, and epidemiological studies suggest that individual variation in genetics and metabolism is a tiny contribution compared to life-long lifestyle choices.

The matrix metalloproteinase (MMP) group of proteins controls a large variety of key physiological and pathological processes, including tissue remodelling, DNA replication, cell-cycle progression, neurodegeneration, and cancer. MMP-2 is constitutively expressed in several tissues and is tightly associated with inflammatory states such as osteoarthritis. MMP-9 is implicated in lipid metabolism and its activity contributes to endothelial dysfunction.

In order to gain insight into the pathophysiology of ageing and to identify new markers of longevity, we analysed the activity levels of MMP-2 and MMP-9 in association with some relevant haematochemical parameters in a Sicilian population, including long-living individuals (LLIs, ≥95 years old). A cohort of 154 healthy subjects (72 men and 82 women) of different ages (age range 20-112) was recruited. The cohort was divided into five subgroups: the first group with subjects less than 40 years old, the second group ranging from 40 to 64 years old, the third group ranging from 65 to 89 years old, the fourth group ranging from 90 to 94 years old, and the fifth group with subjects more than 95 years old.

A relationship was observed between LLIs and MMP-2, but not between LLIs and MMP-9. However, in the LLI group, MMP-2 and MMP-9 values were significantly correlated. Furthermore, in LLIs, we found a positive correlation of MMP-2 with the antioxidant catabolite uric acid and a negative correlation with the inflammatory marker C-reactive protein. Finally, in LLIs MMP-9 values correlated directly both with cholesterol and with low-density lipoproteins. On the whole, our data suggest that the observed increase of MMP-2 in LLIs might play a positive role in the attainment of longevity. This is the first study that shows that serum activity of MMP-2 is increased in LLIs as compared to younger subjects.

Link: https://doi.org/10.1155/2020/8635158

Researchers here propose an interesting approach to restoring vision in cases of age-related macular degeneration. They are using a gene therapy targeted at photoreceptor cells to provide these cells with the ability to be stimulated by near-infrared light. In tests in mice, this appears to function as intended, though it is always challenging to assess the quality of vision (as opposed to its presence or absence) in such experiments.

The main cause of blindness in industrialized countries is the degeneration of photoreceptors, including age-related macular degeneration and retinitis pigmentosa. During the progression of degenerative photoreceptor diseases, light-sensitive and light-insensitive photoreceptor regions in the retina coexist. For example, macular degeneration patients lose vision in the central portion of their retina but retain peripheral eyesight.

Scientists have now succeeded in developing a new therapeutic approach to restore light sensitivity in degenerating retina without negatively affecting remaining vision. They were inspired by species found in nature, such as bats and snakes, that can localize near-infrared light emitted by the bodies of their preys. This is done by using heat-sensitive ion channels which are able to detect the heat of the near-infrared light. This enables the bats and snakes to superimpose thermal and visual images in the brain and thus react to their environment with greater precision.

To equip retinal photoreceptors with near-infrared sensitivity, the researchers devised a three-component system. The first component contains engineered DNA that ensures that the gene coding for the heat-sensitive channel is only expressed in photoreceptors. The second component is a gold nanorod, a small particle, that efficiently absorbs near-infrared light. The third component is an antibody that ensures strong binding between the heat-sensitive channel expressed in photoreceptors and the gold nanorods that locally capture near-infrared light and locally release heat.

The researchers first tested their system in engineered mice with retinal degeneration, confirming that near-infrared light effectively excites photoreceptors and that this signal is transmitted to retinal ganglion cells, the latter representing the output of the retina towards higher visual centers in the brain. Next, they showed that stimulating the mouse eye with near-infrared light is also picked up by neurons in a brain area that is important for conscious vision, the primary visual cortex. They also designed a behavioral test in which untreated blind mice were not able to use near-infrared stimulation to learn a simple task whereas blind mice treated with the three-component system could perform the task related to near-infrared stimulus.

Link: https://www.dpz.eu/en/home/single-view/news/sehvermoegen-durch-gentherapie-wiederherstellen-2.html

The response of governments around the world to the COVID-19 pandemic has essentially shut down the conference circuit for much of 2020. The primary purpose of conferences is networking, and while a number of the conference hosts have organized online events rather than postponing to the end of the year, it just isn't the same. Networking at an online event is a pale shadow of what can be accomplished in the real world. These online conferences do, nonetheless, generate many interesting presentations in the same way as conferences in the real world.

The Longevity Leaders Congress for 2020, the online version of a conference usually held in London, took place at the end of May. In addition to the scheduled discussion panels, a number of companies recorded presentations of their work. These videos are posted to the Longevity Leaders YouTube account. Below I've picked a selection of just the senolytic companies, those focused on the targeted destruction of senescent cells, via quite a diverse set of approaches. There are other companies beyond these, so the full list is worth looking through.

Unity Biotechnology Company Showcase

OneSkin Company Showcase

SIWA Therapeutics Company Showcase

Senolytic Therapeutics Company Showcase

Oisin Biotechnologies Company Showcase

The complement system is a part of the innate immune system, and aids in the coordination of the immune response. It promotes inflammation, and in certain circumstances, such as the loss of blood supply to tissue, known as ischemia, it is actively harmful. Following a stroke, the complement system encourages the immune system to attack and destroy neurons and neural connections in the ischemic area, treating them as though they are dead or debris. A sizable fraction of those brain cells could in principle be salvaged if the blood supply is restored quickly enough, but the complement system actively sabotages this goal. Thus, researchers here propose a targeted interference in the complement system that could aid in limiting the functional damage of a stroke.

Reperfusion therapy, the gold standard for stroke treatment, helps restore blood flow after a stroke caused by a clot, preventing loss of brain tissue. However, only about 10% of stroke patients qualify, in part because of reperfusion therapy's narrow treatment window. New research suggests that this therapy could be both safer and more effective for both motor and cognitive recovery if administered with a specialized compound that blocks the immune response. Reducing the immune response in the brain could be a strategy for improving cognitive recovery. It could also extend the treatment window for therapy, allowing stroke specialists to help many more stroke patients.

"With reperfusion therapy, we're restoring the blood flow, which is necessary to save the tissue, but there is an ongoing inflammatory response by the immune system that is not targeted by reperfusion." This could explain why, though mechanical reperfusion has a success rate of 90% in returning blood flow to the brain, only about 40% of treated patients recover enough motor and reasoning skills within three months to tend to their daily needs independently. Even those who do recover motor function can still struggle with cognitive challenges months later.

During a stroke, the oxygen and energy supply to the brain is cut off by a clot, causing brain tissue to become stressed and die rapidly. Just as it is with a cut to the knee, the immune system is activated to heal the wound, which includes clearing the dead tissue. A family of special immune proteins called complement proteins help to guide and promote this immune response in the damaged areas. These complement proteins flag both dead tissue and stressed brain cells for removal. The stressed brain cells are not yet dead, only damaged by lack of oxygen and energy, and thus salvageable tissue is destroyed by the immune system.

Researchers developed a complement protein blocker, named B4Crry, which acts only at the site of stroke injury. This compound blinds the complement proteins to the signals of stressed brain cells, saving the stressed tissue and reducing overall brain damage. In a mouse model of stroke, reperfusion therapy alone did improve recovery of coordinated movements such as walking. With the addition of B4Crry to treatment, coordinated movement improved even faster, with greater recovery seen as early as three days after the stroke. The improvements to learning and memory were even greater than those seen with motor functions. Reperfusion therapy alone was equal to no treatment at all for learning and memory recovery after stroke. However, when B4Crry was added to their treatments, mice had greatly improved cognitive recovery, making three times fewer errors on a learning and memory task.

After stroke, brain immune cells called microglia began eating the connections between stressed brain cells. Immune system complement proteins were marking these connections for destruction because they displayed the stressed cell signal. Without these connections, brain cells cannot communicate efficiently, and overall brain function decreases. B4Crry concealed the cells' stress signals from the complement proteins and thereby saved the connections between neurons. Preserving connectivity improved learning and memory brain function after stroke.

Link: https://web.musc.edu/about/news-center/2020/06/01/tomlinson

A decellularized organ is one that has had the cells stripped out, such as via detergent solutions, leaving behind the extracellular matrix. Decellularization is a way to obtain a fully detailed organ scaffold, complete with chemical cues to guide the reconstruction of tissues when new cells are added, without having to build it from scratch. That task that is presently impossible, though some groups are making headway in the construction of scaffolds detailed enough for use in tissue engineering. Interestingly, decellularization allows the use of human cells in animal organs: this may be a viable path towards farming pigs for organs that can be recellularized with a patient's own cells and then transplanted without risk of rejection, for example. It remains to be see as to whether this approach stays far enough ahead of efforts to build organs from scratch to have commercial viability.

Using skin cells from human volunteers, researchers have created fully functional mini livers, which they then transplanted into rats. In this proof-of-concept experiment, the lab-made organs survived for four days inside their animal hosts. These mini livers secrete bile acids and urea, just like a normal liver, except they're made-to-order in the lab using patient cells. And, although liver maturation takes up to two years in a natural environment, the researchers did it in under a month.

As an ultimate test, the researchers transplanted their lab-grown mini livers into five rats, who were bred to resist organ rejection. Four days after the transplant, researchers investigated how well the implanted organs were faring. In all cases, blood flow problems had developed within and around the graft, but the transplanted mini livers worked - the rats had human liver proteins in their blood serum.

Researchers are optimistic that this research is not merely a stepping-stone on the path toward growing replacement organs in a lab, but also a useful tool in its own right. "The long-term goal is to create organs that can replace organ donation, but in the near future, I see this as a bridge to transplant. For instance, in acute liver failure, you might just need hepatic boost for a while instead of a whole new liver."

Link: https://www.eurekalert.org/pub_releases/2020-06/uop-lmh052720.php

Exosomes are a popular topic in the regenerative medicine field these days. Exosomes are a class of extracellular vesicle, membrane-bound packages of molecules that cells use as a means of communication. Much of the cell signaling that mediates the benefits of first generation stem cell therapies is in the form of exosomes rather than secreted proteins. Transplanted cells do not survive in large numbers, but their signals do meaningfully affect the behavior of native cells, producing results such as a reduction in chronic inflammation. Exosomes can be easily harvested from cell cultures and are a great deal easier to manage, logistically, than is the case for cells. Thus much of the clinical community presently offering stem cell therapies is shifting focus to exosomes.

Today's open access paper is a look at the delivery of exosomes from mesenchymal stem cells as a basis to treat skin aging. As an approach to therapy, this may function largely by improving clearance of senescent cells. As senescent cells actively maintain chronic inflammation via their secretions, removing them should reduce the chronic inflammation of age and its disruptive effects on skin maintenance. Whether this is the primary mode of action for stem cell therapies or exosome therapies has yet to be rigorously determined. Recent studies suggest that clearance of senescent cells is still ongoing even in older people, but not at a high enough rate to keep their numbers under control. Therapies that adjust clearance rates or creation rates for cellular senescence - as opposed to just directly destroying the excess senescent cells, which is the present focus of the senolytics community - may prove to be useful.

Mesenchymal Stem/Stromal Cell-Derived Exosomes for Immunomodulatory Therapeutics and Skin Regeneration

Aging, defined as irreversible deterioration of physiological processes of organisms over time, is characterized by nine hallmarks: cellular senescence, mitochondrial dysfunction, deregulated nutrient sensing, epigenetic alterations, telomere attrition, genomic instability, altered intercellular communication, and stem cell exhaustion. Among these, cellular senescence has recently been focused on as one of the key factors in the complex aging process as it is interlinked with other hallmarks. Senescent cells are accumulated in tissues of vertebrates with age. Interestingly, removal of senescent cells in animals results in the delayed onset of age-associated diseases.

Senescence is characterized by a stable cell-cycle arrest in the G1 phase and an inflammatory response called senescence-associated secretory phenotype (SASP), which modifies the microenvironment around senescent cells. Components of the SASP include growth factors, pro-inflammatory cytokines, chemokines, and extracellular matrix remodeling enzymes. SASP contributes to inflammaging, a term that describes low-grade, controlled, asymptomatic, chronic, and systemic inflammation associated with aging processes. Evidence points out that inflammaging may ultimately lead to age-related diseases. Thus, interventions that suppress SASP and inflammaging processes may hold potential to alleviate various chronic diseases.

It has been elusive that circulating mediators are responsible for rejuvenating multiple tissues of old organisms by parabiosis of young organisms. Very recently, it was demonstrated that extracellular vesicles (EVs) from young mice plasma extend the lifespan of old mice by delaying aging through exosomal nicotinamide phosphoribosyl transferase (eNAMPT). Another study also reported that exosomes from young mice could transfer miR-126b-5p to tissue of old mice, and reverse the expression of aging-associated molecules. Another report revealed that EVs derived from serum of young mice attenuated inflammaging in old mice by partially rejuvenating aged T-cell immunotolerance. Implantation of hypothalamic stem cells or progenitor cells, which were genetically engineered to survive from aging-related hypothalamic inflammation, was reported to induce retardation of aging and extension of lifespan in mid-aged mice.

More importantly, growing evidence suggests that cellular senescence can be alleviated or reversed by EVs or exosomes derived from stem cells. For example, human exosomes reduced the high glucose-induced premature senescence of endothelial progenitor cells (EPCs) and enhanced wound healing in diabetic rats. Taken together, mesenchymal stem cell derived exosomes confer anti-senescence effects through their unique miRNA, lnRNA, and enzyme contents. By inducing proliferation and reducing SASP in senescent cells, they hold great potential to reduce senescent cells in tissues. Since removal of senescent cells from tissues was reported to create a pro-regenerative environment and tissue homeostasis, application of mesenchymal stem cell derived exosomes to remove the senescent cells may be a preferable approach to induce the regeneration or rejuvenation of tissues.

Researchers here report on their investigations of human astrocytes, a class of supporting cells in the brain that are responsible for maintaining the correct function of neurons. Age-related neurodegenerative conditions have a strong inflammatory component to their progression. The chronic inflammation of aging is thought to drive supporting cells such as astrocytes and glia into harmful behaviors that damage and destroy neurons. This is coming to be seen as an important component of age-related neurodegeneration, and researchers have produced benefits in animal models of neurodegenerative conditions via means of removing the worst of harmful supporting cells in the brain.

Astrocytes, star-shaped cells that make up more than half the cells in the central nervous system, belong to a category of brain cells called glia which provide vital support for neurons in the brain. Astrocytes aid in metabolic processes, regulate connectivity of brain circuits, participate in inflammatory signaling, and help regulate blood flow across the blood-brain barrier, among other duties. They are a crucial component of brain function but are often overlooked in research and drug development, although recent mounting evidence implicates them in many neurological diseases.

"We observed in mice that astrocytes in inflammatory environments take on a reactive state, actually attacking neurons rather than supporting them. We found evidence of reactive astrocytes in the brains of patients with neurodegenerative diseases, but without a human stem cell model, it wasn't possible to figure out how they were created and what they are doing in patient brains."

Researchers used a new human stem cell model to determine if the outcome observed in mice could also be happening in humans. They exposed healthy stem-cell-derived astrocytes to inflammation - essentially mimicking the environment of the brain in neurodegenerative diseases - collected their byproducts, and then exposed these secretions to healthy neurons. "What we saw in the dish confirmed observations in mice: the neurons began to die. Observing this 'rogue astrocyte' phenomenon in a human model of disease suggests that it could be happening in actual patients and opens the door for new therapeutics that intervene in this process."

The team also saw that stem-cell-derived astrocytes exposed to inflammation lost their typical astrocyte functions: they did not support neuronal maturation or firing very well, and they didn't uptake as much glutamate. They also changed their morphology, losing their characteristic 'long arms' and taking on a more constricted star-like shape. "Along with secreting a toxin that kills neurons, we also saw that stem-cell-derived astrocytes in disease-like environments simply do not perform their typical jobs as well, and that could lead to neuronal dysfunction. For example, since they do not take up glutamate properly, too much glutamate is likely left around the neurons, which could cause a neuron to atrophy, and that's something we can potentially target in new therapies."

Link: https://nyscf.org/resources/when-astrocytes-attack-stem-cell-model-shows-possible-mechanism-behind-neurodegeneration/

This popular science article takes a brief look at work on spiroligomers, a solution for some of the hard problems in the design of custom molecules. This might be applied to building molecules that can break glucosepane, the molecule involved in the overwhelming majority of persistent, harmful cross-links in aged human tissues. These cross-links build up with age, linking together structural molecules of the extracellular matrix. This produces a loss of elasticity and increasing stiffness in tissues such as skin and blood vessel walls, the second of which is an important contributing cause of hypertension and consequent cardiovascular disease. Now that glucosepane can be cost-effectively synthesized, an advance funded by the SENS Research Foundation, we should expect to see more novel approaches to drug design being applied to cross-linking.

Christian Schafmeister's academic research is now taking its first steps towards commercialisation in the form of his new start-up - ThirdLaw Technologies. The company seeks to harness the power of 'spiroligomers' to rapidly build new small molecules. "We are starting up a company to develop an artificial immune system. We're making very large libraries of artificial molecules that could bind to protein surfaces. Proteins are these long chains of amino acids that fold into a three dimensional shape and do something amazing - I wanted to build molecules like that. But the problem with proteins and every other approach to this is trying to figure out how this long flexible molecule will fold into a three dimensional shape."

Schafmeister came up with the idea for spiroligomers - using building blocks that are like amino acids but, instead of connecting through one bond, which allows rotational flexibility, his building blocks connect through two bonds. "So you make building blocks that are rings, and you connect them through rings, and so you build ladder molecules,. And you could programme the shape of those ladder molecules by controlling their stereochemistry, the shapes of the rings, and how you put them together."

By achieving this, Schafmeister is able to create molecules that present as reactive groups like the side chains of amino acids, and hold them in a particular three dimensional constellation. This enables spiroligomers to do things like bind protein surfaces, or point them inwards to create pockets that enable catalysis and speed-up select chemical reactions. "The clearest aging-related application for spiroligomers is developing catalysts that can cleave the glucosepane crosslinks. That's a clear goal and something that I think is unique to what we're doing. We could do it in the next year - but it's just a question of resources."

Link: https://www.longevity.technology/building-an-artificial-immune-system/

Heterochronic parabiosis is the name given to the linking of circulatory systems between old and young mice. The old mouse benefits, showing signs of rejuvenation of function, while the young mouse suffers early signs of aging. Initially it was argued that beneficial factors in young blood produce this effect, and a number of efforts moved ahead to produce clinical therapies based on this concept. Some companies like Alkahest have trialed plasma transfer from young to old patients, with so far poor results. Others, like Elevian, are focused on specific factors thought to mediate the effects, GDF11 in that case, and appear to be doing better in their preclinical work.

A presently important debate in the research community is whether or not the benefits of parabiosis are mediated by factors in young blood, or whether it is merely a case of diluting bad factors in old blood. Irina Conboy and Michael Conboy put forward a compelling demonstration a few years ago, using much more controlled method of exchanging blood between old and young animals. It provided very strong evidence for the "bad old blood" hypothesis. Yet there continues to be evidence on the other side suggesting that factors in young blood can produce benefits. Parabiosis is an interesting area of research in this sense.

In the open access paper I'll point out today, the Conboys report on their latest demonstration that parabiosis benefits are the result of dilution of harmful factors in old blood. They develop a means of diluting blood in animals without major disruption to metabolism, and show that it produces very similar benefits to a transfer of young blood. This is, again, quite a compelling argument for the primacy of harmful factors in old blood rather than beneficial factors in young blood in the matter of parabiosis.

Rejuvenation of three germ layers tissues by exchanging old blood plasma with saline-albumin

Historically, the phenomena of heterochronic parabiosis and blood exchange remained unconfirmed with respect to the key assumption as to whether the addition of young factors is needed for rejuvenation, and if premature aging of young mice stemmed from the introduction of old blood factors or a simple dilution of young factors. To answer these questions in a well-controlled experimental set-up, we took advantage of our recently developed small animal blood exchange model.

Here, using our recently developed small animal blood exchange process, we replaced half of the plasma in mice with saline containing 5% albumin (terming it a "neutral" age blood exchange, NBE) thus diluting the plasma factors and replenishing the albumin that would be diminished if only saline was used. Our data demonstrate that a single NBE suffices to meet or exceed the rejuvenative effects of enhancing muscle repair, reducing liver adiposity and fibrosis, and increasing hippocampal neurogenesis in old mice, all the key outcomes seen after blood heterochronicity.

Comparative proteomic analysis on serum from NBE, and from a similar human clinical procedure of therapeutic plasma exchange (TPE), revealed a molecular re-setting of the systemic signaling milieu, interestingly, elevating the levels of some proteins, which broadly coordinate tissue maintenance and repair and promote immune responses. Moreover, a single TPE yielded functional blood rejuvenation, abrogating the typical old serum inhibition of progenitor cell proliferation. Ectopically added albumin does not seem to be the sole determinant of such rejuvenation, and levels of albumin do not decrease with age nor are increased by NBE/TPE.

A model of action (supported by a large body of published data) is that significant dilution of autoregulatory proteins that crosstalk to multiple signaling pathways (with their own feedback loops) would, through changes in gene expression, have long-lasting molecular and functional effects that are consistent with our observations. This work improves our understanding of the systemic paradigms of multi-tissue rejuvenation and suggest a novel and immediate use of the FDA approved TPE for improving the health and resilience of older people.

Researchers here use the transcription levels of hundreds of proteins taken from published nematode study data sets to produce an accurate aging clock, akin to the epigenetic clocks that were the first age assessments of this nature. They then apply much the same process to human data. These clocks are of potential value because they may offer a way to dramatically speed up the process of assessing approaches to rejuvenation, but a great deal more work must be accomplished in order to achieve this goal. At present it is far from clear as to what exactly these metrics are measuring, under the hood. They must thus be calibrated for each and every new type of potential therapy, which rather defeats the point.

Aging clocks dissociate biological from chronological age. The estimation of biological age is important for identifying gerontogenes and assessing environmental, nutritional, or therapeutic impacts on the aging process. Recently, methylation markers were shown to allow estimation of biological age based on age-dependent somatic epigenetic alterations. However, DNA methylation is absent in some species such as Caenorhabditis elegans and it remains unclear whether and how the epigenetic clocks affect gene expression. Aging clocks based on transcriptomes have suffered from considerable variation in the data and relatively low accuracy.

Here, we devised an approach that uses temporal scaling and binarization of C. elegans transcriptomes to define a gene set that predicts biological age with an accuracy that is close to the theoretical limit. Our model accurately predicts the longevity effects of diverse strains, treatments, and conditions. The involved genes support a role of specific transcription factors as well as innate immunity and neuronal signaling in the regulation of the aging process. We show that this transcriptome clock can also be applied to human age prediction with high accuracy. This transcriptome aging clock could therefore find wide application in genetic, environmental, and therapeutic interventions in the aging process.

Link: https://doi.org/10.1101/2020.05.29.123430

Disabling conditions result when the myelin sheathing of nerves is sufficiently degraded, such as via a malfunctioning immune system attacking the body's own tissues, as is the case for multiple sclerosis. All of us suffer loss of myelin with aging to some degree however, due to damage and dysfunction in the oligodendrocyte cell populations responsible for maintaining myelin. There is evidence for this specific issue to contribute to age-related cognitive decline. Thus treatments that focus on boosting remyelination are of general interest: if safe, they should probably be applied to every older person, not just those with conditions such as multiple sclerosis.

Glial cells play several key roles in the central nervous system, including supplying oxygen to neurons and forming myelin - the protective, fatty substance that protects the nerve cells' axons. In multiple sclerosis (MS), glial cells called oligodendrocytes are attacked by the immune system, causing a breakdown of myelin that disrupts the signals between nerve cells and results in a loss of motor and sensory functions.

Researchers are developing a method for regenerating myelin with progenitor glial cells. When they transplanted the cells into mouse models of MS, the cells transformed into new oligodendrocytes and restored myelin. Now, a company that was spun out last year, Oscine Therapeutics, is preparing the cell therapy for human clinical trials in MS and other glial diseases.

In the mouse study, researchers showed that after transplantation, the human glial progenitor cells migrated to damaged areas of the brain. After they created new oligodendrocytes, myelation was restored, as was motor function. Much of the regenerative medicine research in MS is focused on restoring myelin, and several different approaches are under investigation. Last year, researchers reported that when they implanted stem cells with the surface protein CD34 into mouse models of MS, the cells grew into myelin-forming glial cells. Other experimental approaches to regenerating myelin include using microRNAs and reprogrammed skin cells.

Link: https://www.fiercebiotech.com/research/cell-therapy-repairs-multiple-sclerosis-damage-and-restores-motor-functions-mice

Today I'll point out an example of drug reuse and autophagy upregulation. The processes of autophagy are responsible for recycling molecular waste and broken cellular structures. Autophagy is upregulated in response to stress placed upon cells, whether by heat, cold, lack of nutrients, a toxic local environment, and so forth. This is beneficial to tissue function, health, and longevity, and thus there is considerable interest in the research community in producing therapies that boost the operation of autophagy. This hasn't made a great deal of progress towards the clinic, but nonetheless in any of the sizable databases of small molecule compounds there are some that result in increased autophagy - the question is always whether the side-effects are tolerable.

The cancer research community in particular tests a great many compounds and attempts to influence a great many core cellular processes, autophagy included. So when we see attempts at drug reuse, it is often the case that the drug in question is a small molecule that is either present used, used in the past, or was at least considered for chemotherapy. In the trial noted here, the drug is nilotinib. Researchers propose that it produces the observed reduction of toxic protein aggregates in the Alzheimer's disease brain by spurring increased autophagy, and can do so at low enough doses to avoid the worst of the side-effects noted to date. Of course, as is sadly standard in the mainstream of Alzheimer's development, no benefit to patients was observed to accompany improvements in biomarkers. The commentary provided by the trial administrators regarding the need more patients to see possible improvements is what is normally said by trial administrators about treatments that are expected to have only small and unreliable beneficial effects.

This is all par for the course. An entirely too sizable fraction of modern medical development centers not around the development of new therapies, based on new advances in science, but rather finding existing therapies that can be reused in new ways. This, I think, is one of the important underlying reasons as why most new treatments tend to be only marginally effective. The present regulatory structure makes it so costly and difficult to explore new approaches that funding entities are steered into the path of using whatever is already to hand, provided it can be shown to do at least a little good. The edifice of medical development is built of perverse incentives such as this, unfortunately.

Nilotinib Appears Safe and Affects Biomarkers in Alzheimer's Disease Clinical Trial

Nilotinib is approved by the U.S. Food and Drug Administration (FDA) for the treatment of chronic myeloid leukemia. Nilotinib appears to aid in the clearance of accumulated beta-amyloid (Abeta) plaques and Tau tangles in neurons in the brain - hallmarks of Alzheimer's disease. Nilotinib appears to penetrate the blood-brain barrier and turn on the "garbage disposal" machinery inside neurons (a process known as autophagy) to get rid of the Tau, Abeta and other toxic proteins.

After careful screening, 37 people with mild dementia due to Alzheimer's were randomized to either the placebo or nilotinib groups for the 12-month study. A 150 mg daily dose of nilotinib or matching placebo was taken orally once daily for 26 weeks followed by a 300 mg daily dose of nilotinib or placebo for another 26 weeks. To prevent bias the study was blinded, meaning neither the study participants nor the investigators knew if the active drug or placebo were being administered until the end of the study. Nilotinib carries an FDA "black-box warning" because of cardiovascular issues that may lead to sudden death in cancer patients (typically treated with 600 mg daily), but no such incidents occurred in this study (maximum dose of 300 mg daily).

The amyloid burden as measured by brain imaging was reduced in the nilotinib group compared to the placebo group. Two forms of amyloid in cerebrospinal fluid were also measured. Aβ40 was reduced at 6 months and Aβ42 was reduced at 12 months in the nilotinib group compared to placebo. Hippocampal volume loss (on MRI scans of the brain) was attenuated at 12 months and phospho-tau-181 in spinal fluid was reduced at 6 and 12 months in the nilotinib-treated group.

Nilotinib Effects on Safety, Tolerability, and Biomarkers in Alzheimer's Disease

This phase 2 trial was underpowered (as designed) to detect differences in clinical and cognitive outcomes and focused on evidence of nilotinib effects on safety and biomarkers, hence the incongruity between biomarker and clinical effects. Nevertheless, exploratory outcomes included efficacy of nilotinib versus placebo on the change from baseline to 6 months and 12 months. As expected, no differences were observed between the placebo and nilotinib groups on clinical, cognitive, functional, and behavioral outcomes, suggesting that a larger multicenter phase 3 study must be adequately powered to examine potential efficacy. The exploratory clinical outcomes in this phase 2 study will guide the design of an adequately powered larger and longer study to evaluate the safety and efficacy of nilotinib in Alzheimer's disease.

One of the many interesting approaches to targeting cancer cells for destruction is the use of viruses that are largely innocuous to humans, but replicate preferentially in cells exhibiting the characteristics of cancer, such as continual cellular replication. Researchers here demonstrate a way to engineer a virus to require the biochemistry of cell replication for it to also replicate, ensuring that it will affect only cancerous tissue.

Much research in recent years has investigated genetically modifying adenoviruses to kill cancers, with some currently being tested in clinical trials. When injected, these adenoviruses replicate inside cancer cells and kill them. Scientists are trying to design more efficient viruses, which are better able to target cancer cells while leaving normal cells alone. Researchers have now made two new adenoviruses that specifically target cancer cells. To do this, they used adenylate-uridylate-rich elements (AREs), which are signals in RNA molecules known to enhance the rapid decay of messenger RNAs (mRNAs) in human cells. AREs make sure that mRNAs don't continue to code for proteins unnecessarily in cells. Genes required for cell growth and proliferation tend to have AREs.

Under certain stress conditions, however, ARE-containing mRNAs can become temporarily stabilized allowing the maintenance of some necessary cell processes. ARE-mRNAs are also stabilized in cancer cells, supporting their continuous proliferation. Researchers inserted AREs from two human genes into an adenovirus replicating gene, making the new adenoviruses: AdARET and AdAREF. AdARET and AdAREF were both found to replicate inside and kill cancer cells in the laboratory, while they hardly affected normal cells. Tests confirmed that the specific replication in cancer cells was due to stabilization of the viral genes with AREs, which did not happen in the healthy cells. The scientists then injected human cancer cells under the skin of nude mice, which then developed into tumors. When AdARET and AdAREF were injected into the tumors, they resulted in a significant reduction in tumor size.

Link: https://www.global.hokudai.ac.jp/blog/exploiting-viruses-to-attack-cancer-cells/

With few exceptions, the worldwide community of clinics offering first generation stem cell therapies is not usually a source of reliable data. They don't tend to conduct trials or even much report on the results of their work. Further, the stem cell therapies used can vary enormously in effectiveness. Cells are fickle things and tiny differences in how two groups run exactly the same protocol for sourcing and preparing cells can cause widely divergent outcomes, both between clinics, and from patient to patient for the same clinic. Not that groups are in fact usually running the same protocol; a very broad range of possibilities exist under the umbrella term "stem cell therapy." Results in one clinic may not generalize well to other clinics; standardization has been slow to arrive. This is all worth bearing in mind when reading reports such as this one.

For a while now, some plastic surgeons have been using stem cells to treat aging, sun-damaged skin. But while they've been getting good results, it's been unclear exactly how these treatments - using adult stem cells harvested from the patient's own body - work to rejuvenate "photoaged" facial skin. A new microscopic-level study provides the answer: within a few weeks, stem cell treatment eliminates the sun-damaged elastin network and replacing them with normal, undamaged tissues and structures - even in the deeper layers of skin.

The researchers assessed the cellular- and molecular-level effects of mesenchymal stem cells (MSCs) treatment on sun-damaged (photoaged) facial skin. All 20 patients in the study, average age 56 years, were scheduled for facelift surgery. For each patient, a small sample of fat cells from the abdomen was processed to create patient-specific MSCs. The cultured stem cells were injected under the skin of the face, in front of the ear. When the patients underwent facelift surgery three to four months later, skin samples from the stem cell-treated area were compared to untreated areas.

Histologic and structural under the microscope analysis demonstrated that MSC treatment led to improvement in overall skin structure. Treated areas showed "partial or extensive reversal" of sun-related damage to the skin's stretchy elastin network - the main skin structure affected by photoaging. In the layer immediately beneath the skin surface, the stem cell-treated areas showed regeneration of a new, fully organized network of fiber bundles and dermal extracellular matrix remodeling changes. In the deeper skin layer, "tangled, degraded, and dysfunctional" deposits of sun-damaged elastin were replaced by a normal elastin fiber network. These changes were accompanied by molecular markers of processes involved in absorbing the abnormal elastin and development of new elastin.

Link: https://www.eurekalert.org/pub_releases/2020-05/wkh-sct052820.php

Cellular senescence is important in aging. Cells can become senescent in response to damage, a toxic environment, or reaching the Hayflick limit on replication. Senescent cells undergo profound changes to architecture and protein expression that halt replication, cause a growth in size, and produce a potent mix of growth factors and inflammatory signals. Over the short term, this is useful. Senescent cells aid in wound healing and cancer suppression, provided that they are soon destroyed, either by programmed cell death or the immune system. With advancing age, however, senescent cells accumulate in tissues. There is too much creation, while mechanisms of clearance become slow and erratic. The secretions of senescent cells cause chronic inflammation and tissue dysfunction when present over the long term: this is a contributing cause of aging and age-related disease.

Numerous research groups and biotech companies are involved in developing a range of senolytic therapies capable of selectively destroying senescent cells. This is a still comparatively new, but very important branch of medicine. Clearance of senescent cells is literally a rejuvenation therapy, as these errant cells are in effect actively maintaining a degraded state of tissue function. Remove them, and a portion of aging is removed. Numerous age-related conditions have been meaningfully reversed in animal studies of senolytic therapies, including surprising structural reversals such as ventricular hypertrophy.

The promise of this new field of medicine ensures that a great deal of effort is now devoted to mapping the fundamental biochemistry of senescent cells. Scientists are in search of ways to sabotage the survival mechanisms of senescent cells, or their damaging secretions. In that vein, today's open access paper is a review of what is known of the extensive genomic reorganization exhibited by senescent cells. It is almost certainly the case that somewhere in there are novel mechanisms of selective cell destruction that will be discovered and developed for clinical use in the years ahead.

The Histone Code of Senescence

Aging is a physiological condition characterized by the functional deficit of tissues and organs due to the accumulation of senescent cells. The key role of senescence in aging is well-established. Clearance of senescent cells in mouse models delays the appearance of age-related tissue and organ diysfunctions. Senescent cells are characterized by the permanent cell-cycle arrest sustained by the accumulation of cyclin-dependent kinase inhibitors (CDKi), like p16, p21, and p27, as well as by the release of cytokines, chemokines, and soluble factors. This modified microenvironment is known as senescence-associated secretory phenotype (SASP). The senescence state is triggered by different stimuli/stressors. These include the shortening of the telomeres (replicative senescence), the oncogene-induced replication stress, the oncogene-induced senescence (OIS), the accumulation of misfolded protein and/or oxidative stress (stress-induced premature senescence, SIPS).

The impairment of the non-homologous end joining (NHEJ) and homologous recombination (HR) repair mechanisms are common traits of senescent cells. Moreover, a widespread epigenetic resetting characterizes senescent cells and sustains cell-cycle arrest and cellular survival, through the activation of (i) CDKi, (ii) tumor suppressors, and (iii) secretion of chemokines and cytokines, as well as the remodeling of the microenvironment.

Macroscopically, senescent cells are characterized by the formation of peculiar areas of heterochromatin, named as SAHF (senescence-associated heterochromatin foci), mainly at E2F loci. However, SAHF do not characterize all senescent cells and are not causally linked to the onset of senescence. Other epigenetic features, like the distension of satellites (senescence-associated distension of satellites, SADS), the re-activation of transposable elements, and of endogenous retroviruses (ERV), seem to better qualify different types of senescence. Finally, aging appears to be marked by substantial re-arrangements of the nucleosomes, with the loss of histones H3 and H4. During senescence the epigenome undergoes temporal and sequential modifications that are mandatory to accomplish different cellular adaptations. Initially, this epigenetic resetting is mainly due to the accumulation of irreparable DNA damage. After this first wave of epigenetic modifications, the epigenome is remodeled and fixed in order to sustain the permanent cell-cycle arrest and to modulate the microenvironment.

The accumulation of double strand breaks (DSBs) in DNA is a general hallmark of senescence and aging. The main endogenous sources of DSBs are telomere attrition and replicative stress. Replication stress is commonly observed in RS, OIS and aging. In all these conditions cells slow down DNA synthesis and replication fork progression. However, the reduced replication fork speed activates dormant origin to preserve replication timing during replication stress. This adaptive response allows the maintenance of an unaltered replication timing also in cells entering senescence. On the other side it exposes common fragile sites (CFSs), which are genomic loci more prone to breakage after DNA polymerase inhibition, and the accumulation of genomic alterations. CFS alterations are typically observed in pre-neoplastic lesions. Similarly, cells exposed to genotoxic agents (e.g., chemotherapeutic agents, pollutants, and toxins) or to oxidative stress activate the DDR that frequently leads to cell-cycle arrest. Whatever the origin, the accumulation of irreparable DNA damage gives rise to a response characterized by the activation of tumor suppressors and CDKi and by the release of pro-inflammatory cytokines.

Global histone loss, as well as the focused deposition of histone variants (H2AX, H2AZ, H2AJ, H3.3 and macroH2A) and the redistribution of H3K4me3, H3K27me3, and H3K36me3 characterize both DNA damage response, DSBs, and senescence. The chromatin remodeling observed in different senescence models seems to represent a temporal and spatial evolution of what is observed after a short-time treatment of the cells with DNA damaging agents. Cancer cells appear as forgetful cells that have lost the epigenetic memory of a healthy genome. Aging seems to be predisposed to this memory loss. One of the major challenges of the future, regarding the treatment of aging and cancer, will be the identification of the framework of epigenetic changes that can restore this memory.

The processes of autophagy recycle damaged and unwanted structures and proteins in cells. Increased autophagy is involved in the beneficial response to calorie restriction and numerous other mild forms of stress. A range of potential approaches to upregulate autophagy have been explored by the research community, but few have made much progress towards the clinic. It is entirely possible that increased autophagy is more beneficial in some tissues than in others - or to put it another way, perhaps some tissues are much more impaired than others by age-related loss of autophagy. Some of the most impressive data has centered on improved autophagy in the aging liver via LAMP2A upregulation, showing sizable increases in function. Again, these demonstrations have yet to make the transition to clinical medicine.

Aging leads to the accumulation of lipofuscin in the lysosome, which impairs the efficiency of autophagic enzymes. Moreover, aging causes a significant decrease in the number of autophagosomes, which may be related to the decline of activation capacity of AMPK. It further reduces autophagy activity. Liver resection not only triggers liver regeneration, but also induces autophagy of hepatocytes. Autophagy plays a crucial role in liver regeneration. Liver regeneration requires abundant energy, which is among others generated by recycling intracellular macromolecules derived from damaged organelles.

Autophagy activity in aged liver is significantly reduced compared to young liver. Therefore, improving autophagy through pharmacological intervention seems to be an effective treatment to promote regeneration in senescent livers. The mTOR pathway is the most common autophagy-related pathway. However, the mTOR pathway is not only the key regulatory pathway for autophagy, but also the pathway that modulates cell proliferation. Inhibition of mTOR activity can induce autophagy, but inhibits cell proliferation at the same time. In the case of liver resection, inhibition of cell proliferation is detrimental, since it causes impairment of liver regeneration.

Therefore, modulation of autophagy via the mTOR-independent pathway is a better strategy. Strikingly different drugs such as Carbamazepine, Amiodarone, Ezetimibe, and Lithium induce autophagy via these pathways. They are of documented or putative benefit for enhancing liver regeneration and should be explored in more depth. This is of special importance for the elderly population, where liver regeneration is already impaired, in part due to the age-dependent decrease of autophagic activity.

At present, many aging patients with malignant liver disease cannot be treated effectively because of the aging-related impairment of liver regeneration. Aging-related changes also lead to decreased autophagy activity, which is an important cause for insufficient liver regeneration. Age-specific strategies to promote liver regeneration for these patients at risk are needed. Evidence is accumulating that the modulation of autophagy via pharmacological intervention is an effective approach to promote liver regeneration. This is of utmost benefit for aging patients with impaired autophagy. However, choosing the appropriate autophagy pathway to activate autophagy is crucial.

Link: https://doi.org/10.3390/ijms21103606

The ubiquitin-proteasome system is one of the ways in which cells remove damaged and unwanted proteins. Proteins are tagged with ubiquitin, which allows them to enter a proteasome and be broken down into component parts for reuse. Increased proteasomal activity has been shown to be beneficial in short-lived laboratory species, with the understanding that this is because cells will maintain a lower level of damaged components, leading to improved function and lesser degrees of downstream damage. As researchers note here, cells upregulate activity of the ubiquitin-proteasome system in response to mild stress, such as that produced by exercise. This is one of the ways in which exercise produces benefits to health and function.

Physical activity benefits health in many ways, including the building and maintenance of healthy muscles, which are important for our ability to move about normally, as well as to fulfill the vital role of regulating metabolism. Maintaining muscular function is essential. Part of our ability to do so depends upon proteins - the building blocks of muscles - being degraded when worn-out and eliminated in a kind of clean up process that allows them to be replaced by freshly synthesized proteins. Now, researchers have demonstrated that a single, intense, roughly 10-minute bicycle ride results in a significant increase in the activity of ubiquitin and a subsequent intensification of the targeting and removal of worn-out proteins in muscles. This paves the way for an eventual build-up of new proteins.

"Ubiquitin itself is a small protein. It attaches itself to the amino acid lysine on worn-out proteins, after which the protein is transported to a proteasome, which is a structure that gobbles up proteins and spits them out as amino acids. These amino acids can then be reused in the synthesis of new proteins. As such, ubiquitin contributes to a very sustainable circulation of the body's proteins. The important role of Ubiquitin for 'cleaning-up' worn-out proteins in connection with muscular activity was not fully appreciated. Now we know that physical activity increases ubiquitin tagging on worn-out proteins. Basically, it explains part of the reason why physical activity is healthy. The beauty is that muscle use, in and of itself, is what initiates the processes that keep muscles 'up to date', healthy, and functional."

Link: https://nexs.ku.dk/english/news/2020/the-death-marker-protein-cleans-up-your-muscles-after-exercise/

In today's open access paper, the authors survey the work of the past decade in the use of proteomics to assess the consequences of cellular senescence. Senescent cells accumulate with age, but even in late age they remain a tiny fraction of all cells. The harms caused by the long-term presence of senescent cells occur because these cells secrete a potent mix of inflammatory signals, growth factors, and other molecules that rouse the immune system, promote fibrosis and other dysfunctions in tissue maintenance, encourage other cells to also become senescent, and so forth. This senescence-associated secretory phenotype is actually beneficial in the short term: it assists in wound healing and suppression of cancer, for example. As for so many other areas of biochemistry, too much of a good thing is not a good thing at all.

Work progresses on the commercial development of senolytic therapies capable of selectively destroying senescent cells in old tissues. In animal models of numerous age-related conditions, this class of intervention produces consistent and impressive benefits. It is literally a form of rejuvenation, removing cells that are actively maintaining a degraded, damaging state of an aged metabolism. Many age-related conditions have a strong inflammatory component, and those tested are reversed to a meaningful degree by removal of senescent cells and their pro-inflammatory signaling. Interestingly, this field is presently somewhat ahead of the ability to accurately catalog the presence and effects of senescent cells, but many research groups are working on a better understanding of senescent cells and the senescence-associated secretory phenotype. Give it a few years and the scope of available assays will catch up with the ability to remove senescent cells for therapeutic benefit.

The power of proteomics to monitor senescence-associated secretory phenotypes and beyond: toward clinical applications

The development of clinical proteomic biomarkers is an emerging and fast-growing field in human biomedical research. Recently, the focus has been developing senescence-based biomarkers of aging, frailty, and age-related diseases. Over the last decade, proteomic studies of human plasma and other biofluids have made significant progress in accurately quantifying proteins and potential biomarkers at increased depth and coverage. One of the most promising areas for these emerging technologies is therapies that target a fundamental aging process known as cellular senescence.

Cellular senescence is widely accepted as a basic driver of aging and age-related diseases. In this complex stress response, cells permanently lose the ability to proliferate and alter distal tissues through systemic and local paracrine effects. Cellular senescence can be triggered by stressors, including genotoxic agents, nutrient deprivation, hypoxia, mitochondrial dysfunction, and oncogene activation. Although senescent cells irreversibly arrest growth, they remain metabolically active and secrete many biologically active molecules, known as the senescence-associated secretory phenotype (SASP). The SASP initiates inflammation, wound healing, and growth responses in nearby cells. With age, the number of senescent cells or 'senescence burden' increases, and this increased senescence burden and chronic SASP drive many pathological hallmarks of aging.

Cellular senescence is an example of antagonistic pleiotropy - a trait that is beneficial early in life but detrimental later in life. In healthy tissues, the SASP is typically transient and contributes to tissue homeostasis. In contrast, the chronic presence of senescent cells and a SASP is associated with multiple age-related diseases. Eliminating senescent cells and the SASP is considered a highly promising therapeutic strategy for preventing or treating age-associated diseases and extending health span. To selectively kill senescent cells non-genetically, drugs known as 'senolytics' are being developed; additionally, drugs termed senomorphics or senostatics are being developed to mitigate the detrimental effects of senescent cells by modifying the SASP.

To develop clinical therapeutics that target senescent cells, it is critical to have reliable biomarkers to measure the senescent cell burden in humans both to identify patients with an elevated burden and to track the efficacy of the therapeutics. In this review, we will discuss proteomic strategies to discover senescence-derived biomarkers and their great potential for measuring the senescent cell burden. Senescent cells secrete many molecules, and the resulting SASP consists of a complex mixture of both proteins, metabolites, and other molecules. However, thorough investigation is required to determine which SASP protein factors or protein panels qualify as biomarkers to quantitatively assess the senescent cell burden, and subsequently which SASP factors can be used efficiently and accurately as a biomarker for aging and age-related diseases.

Autophagy is the name given to a collection of processes responsible for recycling damaged or otherwise unwanted structures and proteins in the cell. With age, autophagy becomes less efficient. Many individual mechanisms falter, and the end result is that cells become more cluttered with damaged parts and harmful proteins. Scaled up across entire organs, this has a meaningful contribution to the progression of aging and age-related disease. Interestingly, increased or more efficient autophagy appears to be a centrally important mechanism in the benefits to health and longevity provided by calorie restriction and a range of other interventions that mildly stress cells. Accordingly, there is a great deal of interest in the research community in developing therapies based on upregulation of autophagy, though progress towards the clinical has been quite slow so far.

Regular exercise training helps to improve the body's metabolism. The protective effect of exercise on the cardiovascular system has been increasingly recognized in recent years. Exercise can improve the level of cardiac autophagy, promote cardiomyocytes proliferation, reduce local tissue inflammation, and improve cardiac function. Cardiac autophagy plays a crucial role in exercise-induced cardioprotection as a stress response and is a necessary process for adaptation to exercise. However, there are still many questions to be answered in the study of the protective effects and mechanisms of autophagy as they relate to exercise training.

Exercise training for regulating autophagy can be bidirectional. Autophagy impairment and altered autophagy levels have been implicated in the pathogenesis of many diseases. Insufficient autophagy has been reported to contribute to multiple organ dysfunction and other adverse outcomes in autophagy-deficient mice as well as in ill patients, with an observed autophagy deficiency phenotype, evidenced by impaired autophagosome formation, accumulation of damaged proteins and mitochondria, and so on. Excessive autophagy characterized by lysosomal defects and an accumulation of autophagic vacuoles can play an important role in X-linked myopathy. Specifically, for cardiovascular diseases caused by insufficient autophagy, exercise training up-regulates autophagy. For cardiovascular disease caused by excessive autophagy, exercise training can inhibit autophagy, restore regular autophagy function, and delay the progression of cardiovascular disease.

Autophagy is critical in the maintenance of mitochondrial quality and oxidative stress during cardiovascular stress, while exercise can restore protein quality and increase the clearance of reactive aldehydes. Moreover, an increased basal level of cardiac autophagy improves myocardium resistance to subsequent ischemic injury. Aerobic exercise can inhibit the phosphorylation of mTOR by up-regulating the activity of AMPK, thereby improving cardiomyocytes autophagy and preventing cardiac aging and systolic and diastolic dysfunction. A single bout of exercise can also activate autophagy in the heart by activating the transcription factors FOXO3 and hypoxia-inducible factor 1 and then indirectly up-regulating Beclin 1 expression.

Link: https://doi.org/10.1016/j.jshs.2019.10.001

Evidence strongly suggests that the global faltering of mitochondrial function throughout the body with advancing age has a lot to do with a decline in the effectiveness of mitophagy. Mitochondria are the power plants of the cell, a herd of hundreds swarming and replicating like bacteria in every cell to produce the chemical energy store molecule ATP. Mitophagy is the specialized form of autophagy that destroys worn and damaged mitochondria, recycling their component parts. Without it, cells would become overtaken by broken, malfunctioning mitochondria. Mitochondrial dysfunction leads to too little ATP, but also higher levels of harmful oxidative molecules that stress cells. In energy-hungry tissues such as muscle, the heart, the brain, loss of mitochondrial function is thought important in the progression of age-related conditions.

Mitophagy serves as a critical mechanism to eliminate damaged mitochondria and is regulated by multiple mechanistically distinct pathways. Cellular level studies have provided valuable insight into the signaling pathways regulating mitophagy, as well as mapping out how and when mitophagy occurs in a wide range of physiological and pathological conditions to counter cellular stressors such as reactive oxygen species or damaged mitochondria. A better understanding of mitochondrial turnover mechanisms, with an improved focus on how these pathways might contribute to disease pathogenesis, should allow for the development of more efficient strategies to battle numerous pathological conditions associated with mitochondrial dysfunction.

Mitophagy is an important element of overall mitochondrial quality control. Defective mitophagy is thought to contribute to normal aging as well as various neurodegenerative and cardiovascular diseases. In fact, aging by itself is a major risk factor for the pathophysiology of cardiovascular and neurodegenerative diseases. Increasing evidence suggests that mitophagy failure accelerates aging. Interestingly, a marked age-dependent decline in mitophagy has been observed in the hippocampus of the mouse brain, an area where new memory and learning are encoded. This strengthens the hypothesis that mitophagy might regulate neuronal homeostasis and that a decline in mitophagy might predispose to age-dependent neurodegeneration. Age-related mitochondrial function deterioration is underlined as a key feature of other diseases, such as obesity, diabetes, and cancer. Therefore, maintaining a healthy mitochondrial network via functional mitophagy may serve as an attractive therapeutic strategy in the treatment of a wide range of age-related diseases, and potentially regulate longevity.

The emergence of nutritional and pharmacological interventions to modulate autophagy/mitophagy and to serve as a potential therapeutic model is quite encouraging. Accumulation of ubiquitinated outer mitochondrial membrane proteins has been proposed to act as a signal for selective mitophagy. Ubiquitination of mitochondrial proteins is positively regulated, in part, by the E3 ubiquitin ligase, Parkin. In contrast, removal of ubiquitin is achieved by the action of resident mitochondrial deubiquitinases, most notably USP30, thereby acting to antagonize mitophagy. Inhibition of USP30 enzyme activity may provide an unambiguous avenue to pursue the role of mitophagy as a therapeutic target.

Recently, three promising candidates that may stimulate and reinvigorate mitophagy process have been demonstrated to reduce the accumulation of amyloid-beta and phosphorylated tau in Alzheimer's mouse brains. These compounds, including nicotinamide mononucleotide, urolithin A, and actinonin, can improve symptoms of AD and dementia symptoms in preclinical models. In addition, Tat-Beclin 1 peptide, derived from a region of the autophagy protein, beclin 1, can promote autophagy/mitophagy and improve mitochondrial function in heart failure animal models. Therefore, identifying more efficient and specific agents that can modulate the clearance of defective mitochondria are likely to have significant therapeutic benefits.

Link: https://doi.org/10.3389/fcell.2020.00294

Aging as we understand it is almost a universal phenomenon in animals. Clearly there is something advantageous in evolutionary terms in having disposable individuals carry the immortal germline forward in time. One possibility is that aging is an emergent property of the fact that selection pressure is always going to fall more heavily on younger individuals, and thus evolution favors change in the direction of biological systems that are highly effective in youth but fall apart later on. Resources directed towards long-term maintenance subtract from resources directed towards immediate reproductive success. It is a brutal zero-sum race to the bottom, driven by the mortality of predation and a hostile environment. Younger individuals contribute more to the fitness of a species, because fewer of them have been eaten or otherwise removed from the picture.

Another view is that immortal species do have certain advantages in certain situations, and will emerge over time in any period of stability. They will vanish in eras of environmental change or hardship, however, outcompeted by species that age, as aging makes them more likely to adapt successfully. This viewpoint predicts the present situation, in which there exist only a very few species that appear not to age (as for hydra), or to age negligibly to various degrees (lobsters, sea urchins, naked mole-rats, and so forth). But at root, these evolutionary theories are all based on models and hypotheses, and thus prone to shift in and out of favor over time. Proof is hard to come by in this field.

Some varieties of sea urchin are among the small number of species that show very few signs of aging. Like many of their negligibly senescent peers they are capable of proficient regeneration, and the details of their aging (or lack of said) is in fact quite poorly studied in comparison to what is known of mammalian biochemistry in unusually long-lived species such as naked mole-rats. Even simpler data can be poorly characterized: maximum life span is an entirely speculative number for many sea urchin species, for example. It is only known that the number is quite large.

Senescence and Longevity of Sea Urchins

Echinoids, known as sea urchins, are a relatively small class of marine invertebrates with just over 1000 extant species. Historically, sea urchins served as model organisms in developmental biology. Later on, their properties were expanded to studying the innate immune system. Recently, the sea urchin was suggested as a novel model for studying longevity and senescence. Sea urchins are organisms of great lifespan diversity; some of which show extreme longevity. A noteworthy example is the red sea urchin, Mesocentrotus franciscanus, which has been confirmed to live well over 100 years with some specimens reaching 200 years. Conversely, the green sea urchin, Lytechinus variegatus, has an estimated maximal life expectancy of only four years. The lifespan diversity between different sea urchin species and the extreme longevity that some species achieve raises questions about their aging process. Do sea urchins age? Are there any indications of aging?

Aging in many organisms is accompanied by the complex mechanism of senescence, which involves a substantial number of biological processes which have different characteristics, such as genomic instability, telomere shortening, mitochondrial dysfunction, loss of proteostasis, stem cell exhaustion, and changes in intracellular communications. In some multicellular organisms, these processes can be so slow to the point where they might be considered negligible. Organisms that fit the criteria for negligible senescence display no noticeable increase in age-specific mortality or decrease in reproduction rate with age, as well as no noticeable weakening in their physiological capacity or disease resistance. Sea urchins grow indeterminately and reproduce throughout their entire adult life.

The lack of age-associated telomere shortening has been observed in both long-lived and short-lived sea urchins. Analysis from several adult M. franciscanus samples indicated continuous telomerase expression and maintenance of telomeres. Lifelong telomerase activity was also reported in another species of sea urchin, Echinometra lucunter. Even though telomere shortening has been suggested to be a tumor-protective mechanism and despite neoplasia occurring in diverse species of marine invertebrates, neoplasms are rarely seen in sea urchins.

Sea urchins do not fit within the classic understanding of biological aging. Members of this class are among the oldest animals on earth and it is apparent that the hallmarks of aging do not apply in their case. Considering the lack of senescence and sequencing revealing a genetic relation to humans, it is clear why researchers suggest the sea urchin is a novel model for studying aging. However, the research on sea urchins from that point of view is relatively new. At the end of the last century, even the centenarian sea urchin M. franciscanusm was thought to live just above 30 years. It was only in 2003 that carbon-14 dating exposed evidence of nuclear weapon testing from the 1950s in tissues of M. franciscanus and thus confirmed its exceptional lifespan. Further, work from 2012 was, to the best of our knowledge, the first and only global approach study on age-related gene expression in sea urchins. Since the evidence of negligible senescence is similar across short- and long-lived sea urchins, the mechanism of their mortality remains poorly understood. Therefore, further research is required.

Exercise is known to improve outcomes in heart failure patients, but there is a limit as to the data that can be obtained on mechanisms of action from human patients. Here researchers use a mouse model of heart failure to show that exercise doesn't impact the harmful presence of fibrosis in heart tissue, but does increase capillary density. The density of capillaries in tissues throughout the body declines with age, and this progressive loss is probably quite important in a number of aspects of aging, particularly in tissues that have high energy demands, such as the heart. That fibrosis isn't affected suggests that exercise doesn't do much to reduce the burden of cellular senescence, however, given that senescent cells are strongly implicated in age-related fibrosis.

Heart failure with preserved ejection fraction (HFpEF) is the most common type of heart failure in older adults. Although no pharmacological therapy has yet improved survival in HFpEF, exercise training has emerged as the most effective intervention to improving functional outcomes in this age-related disease. The molecular mechanisms by which exercise training induces its beneficial effects in HFpEF, however, remain largely unknown. Given the strong association between aging and HFpEF, we hypothesized that exercise training might reverse cardiac aging phenotypes that contribute to HFpEF pathophysiology and additionally provide a platform for novel mechanistic and therapeutic discovery.

Here, we show that aged (24-30 months) C57BL/6 male mice recapitulate many of the hallmark features of HFpEF, including preserved left ventricular ejection fraction, subclinical systolic dysfunction, diastolic dysfunction, impaired cardiac reserves, exercise intolerance, and pathologic cardiac hypertrophy. Similar to older humans, exercise training in old mice improved exercise capacity, diastolic function, and contractile reserves, while reducing pulmonary congestion.

Interestingly, RNAseq showed that exercise training did not significantly modulate biological pathways targeted by conventional HF medications. However, it reversed multiple age-related pathways, including the global downregulation of cell cycle pathways seen in aged hearts, which was associated with increased capillary density, but no effects on cardiac mass or fibrosis. Taken together, these data demonstrate that the aged C57BL/6 male mouse is a valuable model for studying the role of aging biology in HFpEF pathophysiology, and provide a molecular framework for how exercise training potentially reverses cardiac aging phenotypes in HFpEF.

Link: https://doi.org/10.1111/acel.13159

One possible expansion of present immunotherapies for Alzheimer's disease is to more specifically track and target oligomeric forms of amyloid-β. Efforts to reduce amyloid-β in the brain have, after many years of failure, started to succeed in that goal in human trials, but patients are not exhibiting benefits as a result. It remains to be seen whether or not this is because amyloid-β is a trigger for other self-sustaining pathological mechanisms, such as cellular senescence of supporting cells in the brain, and thus removing it does little good once Alzheimer's is underway. An alternative view is that perhaps the wrong forms of amyloid-β are being targeted by existing approaches, and a more specific therapy would achieve better results.

Researchers have designed an antibody which is highly accurate at detecting toxic amyloid-beta oligomers and quantifying their numbers. "There is an urgent unmet need for quantitative methods to recognise oligomers - which play a major role in Alzheimer's disease, but are too elusive for standard antibody discovery strategies. Through our innovative design strategy, we have now discovered antibodies to recognise these toxic particles."

Alzheimer's disease, the most prevalent form of dementia, leads to the death of nerve cells and tissue loss throughout the brain, resulting in memory failure, personality changes and problems carrying out daily activities. Abnormal clumps of proteins called oligomers have been identified by scientists as the most likely cause of dementia. Although proteins are normally responsible for important cell processes, according to the amyloid hypothesis, when people have Alzheimer's disease these proteins - including specifically amyloid-beta proteins - become rogue and kill healthy nerve cells.

Proteins need to be closely regulated to function properly. When this quality control process fails, the proteins misfold, starting a chain reaction that leads to the death of brain cells. Misfolded proteins form abnormal clusters called plaques which build up between brain cells, stopping them from signalling properly. Dying brain cells also contain tangles, twisted strands of proteins that destroy a vital cell transport system, meaning nutrients and other essential supplies can no longer move through the cells.

"While the amyloid hypothesis is a prevalent view, it has not been fully validated in part because amyloid-beta oligomers are so difficult to detect, so there are differing opinions on what causes Alzheimer's disease. The discovery of an antibody to accurately target oligomers is, therefore, an important step to monitor the progression of the disease, identify its cause, and eventually keep it under control." The lack of methods to detect oligomers has been a major obstacle in the progress of Alzheimer's research. This has hampered the development of effective diagnostic and therapeutic interventions and led to uncertainty about the amyloid hypothesis.

Link: https://www.cam.ac.uk/research/news/antibody-designed-to-recognise-pathogens-of-alzheimers-disease

There is evidence for particulate air pollution to raise the risk of age-related diseases via mechanisms such as increased levels of chronic inflammation. While the burden of age-related disease varies widely from region to region, establishing the relative weight of specific contributions is a challenge. Poverty, particulate air pollution, high rates of chronic infection, and other environmental factors thought likely to lead to a greater risk of age-related disease all tend to overlap to some degree.

Thus while there are plausible mechanisms for particulate air pollution to spur chronic inflammation and thus speed the onset of age-related disease, and these mechanisms are well-demonstrated in laboratory animals, one cannot rule out the possibility that it is nonetheless the case that much of the observed differences in life expectancy and incidence of age-related conditions in human populations are primarily a result of worse access to medical resources. Or differences in culture that lead to differing levels of physical activity or differences in diet that add up over time. And so forth.

That said, some of the more recent epidemiological research on this topic uses comparison populations that allow for the elimination of most of the uncertainties. The results strongly suggest that exposure to wood smoke or exposure to coal smoke accelerates cardiovascular disease and reduces life expectancy. It isn't just cardiovascular disease: all of the more common age-related conditions with a strong inflammatory component are candidates for this sort of effect. That includes forms of dementia, as the two articles here discuss.

Air Pollution and Dementia - Through Hazy Data, Links Emerge

Overall, scientists are reporting that people with the highest exposures to pollutants are more likely to get dementia. Some of the risk may lie in chronic deterioration of the cardiovascular and cerebrovascular systems. Alas, researchers are finding that particulate matter can also get into the brain through olfactory nerves or across the blood-brain barrier, whereupon they may affect neurons and glia directly. Diffuse Aβ plaques, hyperphosphorylated tau, and aggregates of α-synuclein have been detected in olfactory bulbs in the brains of young people who lived in Mexico City, where air pollution is high.

With the field heating up, are epidemiologists ready to claim that air pollution increases a person's risk for dementia? "I think we are comfortably suspicious. The toxicology suggests it is biologically plausible, but there's a lot of diversity in the exposure and outcome data. Air pollution is similar to other risk factors. There is a signal that may be far from certain but is strong enough to warrant more attention." Some researchers call air pollution a gerogen. "It accelerates aging, weakens blood vessels in the brain, and promotes amyloid production. The argument that air pollution is a risk factor for dementia is doubly strong because it also accelerates atherosclerosis, which is a risk factor independently of everything else."

The Air We Breathe - How Might Pollution Hurt the Brain?

For decades, studies of pulmonary and vascular systems dominated the air-pollution-research landscape. Researchers paid scant attention to the brain, which they considered safely ensconced behind the blood-brain barrier. But the science has begun to change. Evidence has been steadily trickling in that exposure to ambient air pollution, even at levels near the upper limits set by the World Health Organization, can affect the central nervous system. ver the last decade, numerous epidemiological studies have tied pollution to increased risk for cognitive decline and dementia.

Though the data is often equivocal, scientist are asking just how do pollutants damage the brain? Chronic deterioration of the cardiovascular and cerebrovascular systems may be to blame, but researchers are also finding that particulate matter gets into the central nervous system, either through olfactory nerves or across the blood-brain barrier, and then harms neurons and glia directly. Olfactory nerves in the nose carry a variety of cargo into the brain. In the case of pollutants, the research has focused on ultrafine particles (UFPs). At less than 0.1 micrometers in diameter, UFPs are even smaller than PM2.5. The EPA does not regulate them, hence they are not routinely monitored in the U.S. Researchers are setting up their own monitoring equipment to measure levels in ambient air that is pumped into animal facilities. While this research is still coming in, it already indicates these small particles could be particularly harmful. "This has become a topic of great interest, but we need much more data on the olfactory system."

BCL-xL is a mitochondrial protein that acts to suppress the programmed cell death response of apoptosis, and is overexpressed in some cancers, as well as in senescent cells. Thus small molecules that bind to BCL-xL have been used as chemotherapeutics and more recently as senolytics that selectively destroy senescent cells. That removal of senescent cells is a legitimate rejuvenation therapy that quite literally turns back aging in animal models has caused greater attention to be given to BCL-2 family proteins and their role in allowing cells to hold back apoptosis.

Separately, as noted here, evidence shows that BCL-xL is a longevity-associated protein, which is interesting, to say the least. This may or may not have anything to do with suppression of apoptosis - or if it does, one has to argue that keeping apoptosis-inclined cells alive for longer is on balance beneficial, despite being detrimental in the matter of senescent cells, or that apoptosis is complex and situational. This may be the case, but it is always challenging to tease out the specific contributions to any observed outcome of this nature. Another possibility is that greater levels of BCL-xL improve mitochondrial function in some way, but more work is needed to establish whether or not this is a plausible mechanism.

We have studied centenarians, as an example of successful aging, and have found that they overexpress BCL-xL. By performing functional transcriptomic analysis of peripheral blood mononuclear cells (PMBC), we compared the expression patterns of 28,869 human genes in centenarians, septuagenarians, and young people. Results showed that the mRNA expression pattern of centenarians was similar to the one of young people, and completely different from that of septuagenarians. In particular, sub-network analysis of the 1,721 mRNAs that were found to be statistically different between the three populations, converged on the following six genes: interferon-γ (IFNG), T-cell receptor (TCR), tumor necrosis factor (TNF), SP1 transcription factor, transforming growth factor-β1 (TGFβ1), and cytokine IL-32.

Likewise, those six genes were related to BCL-xL, Fas, and Fas ligand (FasL), all of them known to be involved in the control of cell death regulation. However, where BCL-xL is an antiapoptotic protein, Fas and FasL are proapoptotic. This could be considered a paradox, as centenarians overexpress anti and proapoptotic proteins at the same time, but there is an explanation: BCL-xL is involved in the inhibition of the intrinsic pathway of apoptosis, which is mainly mediated by mitochondria and activated after self-cell stress; however, Fas and Fas-L induce the extrinsic pathway of apoptosis, which means that they force the cell to die after external stress signals. This suggests that centenarians have a better way to control apoptosis when cells are aging (intrinsic apoptosis), but at the same time, damaged cells by external signals are removed more efficiently (extrinsic apoptosis).

In order to further demonstrate the role of BCL-xL in longevity, we performed longevity curves using C. elegans with a gain function of Ced-9, the ortholog for human BCL-xL. Interestingly, animals overexpressing Ced-9 showed a significant increase in both the mean and the maximum survival time. Although aging is a multifactorial process, these studies suggest that BCL-xL function is relevant in aging and may be one of the factors that contributes to exceptional longevity.

Link: https://doi.org/10.3390/ijms21020418

In most species, including our own, females live longer than males. Why this is the case is likely one of those simple questions that lacks a simple answer. At the root of it all are evolutionary pressures relating to sex-specific differences in mating strategy, but that says little about how and why an emergent property such as sex-specific life span differences actually emerges. Researchers here find a great deal of variation from species to species in the degree of the female longevity advantage, complicating the picture.

The researchers compiled demographic data for more than 130 wild mammal populations and were able to estimate the average longevity and the rate of increase in the risk of dying as a function of age for both sexes. The analyzes led to unexpected results. Not only do females generally live longer than males in wild mammals, but the difference in longevity between the sexes, although very variable depending on the population, in the vast majority of cases exceeds the difference observed in human populations. The average female wild mammal lives 18.6% longer than her male counterpart. In humans the difference is "only" 7.8%. The greatest differences are found in animals like Common brushtail possum, lion, killer whale, moose, greater kudu, and sheep.

For about half of the mammal populations studied, the increased risk of mortality with age is actually more pronounced in females than in males. These results show that the larger longevity of females than males is most likely due to other factors that affect individuals during their entire adult life. To reach this conclusion, researchers calculated the average age at death, as well as the rate at which mortality increases with age.

There is a common belief that males engage in potentially dangerous sexual competitions and live riskier lives than females, and that this could account for their shorter lifespan. Contrary to this idea, this study reveals that the intensity of sexual selection does not directly modulate the amplitude of the differences in longevity observed between the sexes. The results rather suggest that complex interactions between the physiological characteristics specific to each sex and local environmental conditions are at play.

Why do the females live longer? One explanation is that males often are larger and put more energy in sexual characters such as growing larger horns than females. This requires energy, and if the animals live in a harsh climate, the males may be more vulnerable to these extreme environmental conditions. Another explanation is that males produce more androgens than females. Androgens modulate immune performance and when present at high levels, they can impair some aspects of the immune defense, making males more susceptible to infections and diseases.

Link: https://www.sdu.dk/en/nyheder/forskningsnyheder/vildtlevende-hunner-lever-laengere-end-hanner