Fight Aging! Newsletter, May 23rd 2022

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  • Immunization Against Amyloid-β Aggregation as a Strategy to Treat Alzheimer's Disease
  • Removal of Lipofuscin Extends Life in Nematode Worms
  • Naked Mole-Rat Skin Shows Fewer Signs of Aging
  • Cerebrospinal Fluid Transfer from Young Mice Improves Memory in Old Mice
  • The Safe, Largely Ineffective End of Biogerontology
  • Wanting a Longer Life Correlates with Achieving a Modestly Longer Life
  • Senescent Cell Extracellular Vesicles in Vascular Calcification
  • Lower Physical Performance Correlates with Some Inflammation Markers
  • Pathogenic Viruses Have Evolved to Provoke Cellular Senescence
  • Human Genetic Variants Associated with Longevity are Also Associated with Cardiovascular Health
  • YAP Upregulation to Reduce Astrocyte Senescence in the Aging Brain
  • João Pedro de Magalhães on Rejuvenation Therapies
  • T Cells Implicated in Age-Related Impairment of Nerve Regeneration
  • Branched-Chain Amino Acids in the Context of Protein Restriction
  • Parabiosis Slows Aging of the Gut Microbiome in Mice

Immunization Against Amyloid-β Aggregation as a Strategy to Treat Alzheimer's Disease

The prevailing view of Alzheimer's disease continues to be the amyloid cascade hypothesis, that a slow age-related accumulation of misfolded amyloid-β causes sufficient dysfunction to set the stage for later pathology involving senescent cells, chronic inflammation, and aggregation of altered tau protein. That later pathology is much more destructive, self-sustaining enough for removal of amyloid-β, now successfully achieved in a number of immunotherapy clinical trials, to be of little use to patients.

It remains that case that the research community sees removal of amyloid-β as a potential way to prevent the development of Alzheimer's disease, assuming sufficiently early and sustained intervention to maintain low levels of amyloid-β aggregation throughout life. Today's open access paper discusses an immunization approach: direct the immune system to destroy excess amyloid-β by provoking it into recognizing a part of the amyloid-β protein as foreign.

The interesting unresolved question continues to be why amyloid-β aggregation is an age-related process. A growing faction within the research community question whether amyloid-β accumulation is actually an important contributing cause of Alzheimer's disease, versus being a side-effect of other, more relevant processes. For example, amyloid-β is an anti-microbial peptide, a component of the innate immune system, and it may be that increased levels of amyloid-β are a feature of persistent vital infection that drives chronic inflammation, where that inflammation is the true driving pathology.

Study preserves memory in mice, offering promising new basis for active immunization against Alzheimer's disease

Researchers have discovered a possible new approach to immunization against Alzheimer's disease (AD). Their method uses a recombinant methionine (Met)-rich protein derived from corn that was then oxidized in vitro to produce the antigen: methionine sulfoxide (MetO)-rich protein. This antigen, when injected to the body, goads the immune system into producing antibodies against the MetO component of beta-amyloid, a protein that is toxic to brain cells and seen as a hallmark of Alzheimer's disease.

"As we age, we have more oxidative stress, and then beta-amyloid and other proteins accumulate and become oxidized and aggregated - these proteins are resistant to degradation or removal. In a previous 2011 published study, I injected mouse models of Alzheimer's disease with a similar methionine sulfoxide-rich protein and showed about 30% reduction of amyloid plaque burden in the hippocampus, the main region where damage from Alzheimer's disease occurs."

The MetO-rich protein used for the vaccination of AD-model mice is able to prompt the immune system to produce antibodies against MetO-containing proteins, including MetO-harboring beta-amyloid. The introduction of the corn-based MetO-rich protein (antigen) fosters the body's immune system to produce and deploy the antibodies against MetO to previously tolerated MetO-containing proteins (including MetO-beta-amyloid), and ultimately reduce the levels of toxic forms of beta-amyloid and other possible proteins in brain.

Protective Effects against the Development of Alzheimer's Disease in an Animal Model through Active Immunization with Methionine-Sulfoxide Rich Protein Antigen

The brain during Alzheimer's disease (AD) is under severe oxidative attack by reactive oxygen species that may lead to methionine oxidation. Oxidation of the sole methionine of beta-amyloid (Aβ), and possibly methionine residues of other extracellular proteins, may be one of the earliest events contributing to the toxicity of Aβ and other proteins in vivo. In the current study, we immunized transgenic AD (APP/PS1) mice at 4 months of age with a recombinant methionine sulfoxide (MetO)-rich protein from Zea mays (antigen). This treatment induced the production of anti-MetO antibody in blood-plasma that exhibits a significant titer up to at least 10 months of age.

Compared to the control mice, the antigen-injected mice exhibited the following significant phenotypes at 10 months of age: better short and long memory capabilities; reduced Aβ levels in both blood-plasma and brain; reduced Aβ burden and MetO accumulations in astrocytes in hippocampal and cortical regions; reduced levels of activated microglia; and elevated antioxidant capabilities (through enhanced nuclear localization of the transcription factor Nrf2) in the same brain regions.

Removal of Lipofuscin Extends Life in Nematode Worms

Lipofuscin is a mix of many forms of persistent metabolic waste that accumulates with age in the lysosomes of long-lived cells, such as those of the central nervous system. This degrades the effectiveness of cellular recycling mechanisms, as they depend upon the delivery of materials to lysosomes, where they are broken down. A lysosome is a membrane packed with molecular tools to break down near everything a cell will encounter, but (a) it struggles with some compounds, and (b) becomes impaired in old tissues, and hence the existence of lipofuscin.

Targeted removal of lipofuscin is an important strategy in the rejuvenation toolkit. As of yet only partially effective approaches are available, unfortunately. Like the example here, these depend on adjusting metabolism in ways that provoke greater cellular housekeeping efforts, more efficient lysosomal function.

Plausibly, this will only work for some of the many different problem molecules that make up lipofuscin, those are are less resilient to being broken down, that only accumulate to cause pathology as a result of age-related declines in cellular maintenance. While we have the one impressive example of liver function rejuvenation as a result of improving lyosomal function with LAMP2A upregulation, in general the strategy of upregulating cellular maintenance doesn't work as well to extend life in long-lived species as it does in short-lived species. This is well demonstrated in the few examples we can compare directly, such as the practice of calorie restriction.

Remofuscin induces xenobiotic detoxification via a lysosome-to-nucleus signaling pathway to extend the Caenorhabditis elegans lifespan

Lipofuscin is a representative biomarker of aging that is generated naturally over time. Remofuscin (soraprazan) improves age-related eye diseases by removing lipofuscin from retinal pigment epithelium (RPE) cells. In this study, the effect of remofuscin on longevity in Caenorhabditis elegans and the underlying mechanism were investigated. The results showed that remofuscin significantly extended the lifespan of C. elegans compared with the negative control. Aging biomarkers were improved in remofuscin-treated worms.

The expression levels of genes related to lysosomes (lipl-1 and lbp-8), a nuclear hormone receptor (nhr-234), fatty acid beta-oxidation (ech-9), and xenobiotic detoxification (cyp-34A1, cyp-35A1, cyp-35A2, cyp-35A3, cyp-35A4, cyp-35A5, cyp-35C1, gst-28, and gst-5) were increased in remofuscin-treated worms. Moreover, remofuscin failed to extend the lives of C. elegans with loss-of-function mutations (lipl-1, lbp-8, nhr-234, nhr-49, nhr-8, cyp-35A1, cyp-35A2, cyp-35A3, cyp-35A5, and gst-5), suggesting that these genes are associated with lifespan extension in remofuscin-treated C. elegans.

In conclusion, remofuscin activates the lysosome-to-nucleus pathway in C. elegans, thereby increasing the expression levels of xenobiotic detoxification genes resulted in extending their lifespan.

Naked Mole-Rat Skin Shows Fewer Signs of Aging

Naked mole-rats exhibit a maximum life span that is many times longer than is the case for similarly sized mammals. Further, they are negligibly senescent, showing few age-related declines in function across much of that lengthy life span. That includes maintenance of stem cell populations and regenerative capacity, as well as a near immunity to cancer. Accordingly, the research community is very interested in uncovering the genetic and biochemical differences that allow naked mole-rats to achieve these desirable outcomes.

In today's open access paper, the authors report on their investigation of the biochemistry and aging of naked mole-rat skin. The skin in this species, like other organs, shows few signs of degenerative aging in comparison to other mammals. The maintenance of stem cell populations may be one of the more important aspects of this resilience to aging, but there are a few other surprises. Clearly some gene expression in the skin is changing in the latter half of life, but that does not appear to greatly impact the more important functions.

It is interesting to speculate as to how it is that gene expression can change while function remains youthful. What is actually changing under the hood? For example, it is known that naked mole-rats do accumulate senescent cells with age, but those senescent cells do not exhibit the harmful behavior found in other mammals. Further, naked mole-rats show signs of oxidative damage to cells with age, but that damage doesn't appear to produce the consequences observed in other mammals.

Single-cell transcriptomics reveals age-resistant maintenance of cell identities, stem cell compartments and differentiation trajectories in long-lived naked mole-rats skin

Constantly exposed to both internal and environmental stresses such as UV radiation or air pollutants, the skin ages and undergo profound changes in its appearance and functions. Indeed, aged skin undergoes gradual structural and functional degeneration, leading to thinning of epidermal and dermal layers, loss of elasticity, wrinkling, and dryness. These changes are responsible for delayed wounding, more frequent infections, pruritus, enhanced allergen/irritant penetrations with variable degree of dermatitis and eventually carcinogenesis. In rodents and humans, these phenomena have been partially attributed to loss or lineage skewing of keratinocytes stem cells and immune cells, and/or the regulation of their niches, altering normal homeostasis and tissue repair.

Naked mole-rats (NMRs) are small poikilothermic and hairless rodents native to East Africa, where they live underground in eusocial colonies. These mouse-sized rodents live almost five times longer than expected on the basis of body size, with a maximum lifespan exceeding 37 years in captivity and up to 17 years in their natural habitat. Despite being the longest-lived rodent, NMR do not show any increase in age-specific hazard of mortality in defiance of Gompertz's law and all of the classical signs of aging such as decreased fertility, muscle atrophy, bone loss, changes in body composition or metabolism seem to be mostly absent in these animals.

We used single-cell RNA-sequencing (scRNA-seq), to obtain the unbiased molecular RNA profile of the NMR epidermal cell populations. By profiling 10,000+ cells from skin epidermis in young and older NMR, we found that epidermal compartments and cell populations, especially the stem cells pool, remained unaffected despite aging. Igfbp3, expressed by keratinocyte stem cells and known to play a major role during epidermal homeostasis, was found upregulated in older animals, contrary to what is observed in other species. In addition, functional skin healing experiments revealed that NMR skin healing closure was similar in young and older animals.

Cerebrospinal Fluid Transfer from Young Mice Improves Memory in Old Mice

Researchers have for some time investigated the effects of transfusing materials from young animals to old animals, largely blood fractions such as blood plasma, but also other line items such as samples of the gut microbiome, thymic tissue, and so forth. The work on blood and plasma transfusions from young to old has proven disappointing in comparison to parabiosis, in the sense that results have been mixed, both in mice and in human trials. Transferring gut microbes to rejuvenate the aged intestinal microbiome looks much more promising.

In today's research materials, scientists report on a more challenging procedure, the transfer of cerebrospinal fluid between mice. Young cerebrospinal fluid improves brain function in old mice, leading to benefits to memory. Based on watching more than a decade of debate over the mechanisms involved in the way in which young blood may benefit old animals, a debate that is still very much ongoing, I expect that it will no doubt be some years before the scientific community comes to a good understanding of the mechanisms involved in improvements to cognitive function resulting from exposure to young cerebrospinal fluid.

Young brain fluid improves memory in old mice

Cerebrospinal fluid (CSF) from young mice can improve memory function in older mice. A direct brain infusion of young CSF probably improves the conductivity of the neurons in ageing mice, which improves the process of making and recalling memories. The researchers also isolated a protein from the CSF cocktail that another analysis had suggested was a compelling candidate for improving memory: fibroblast growth factor 17 (Fgf17). Infusion of Fgf17 had a similar memory-restoring effect to infusing CSF. Furthermore, giving the mice an antibody that blocked Fgf17's function impaired the rodents' memory ability.

It took more than a year to perfect the process of collecting CSF and infusing it into another brain. Collection is extremely challenging, and has to be done with precision. Any blood contamination will ruin the fluid. Pressure in the brain is a delicate balance, so infusion must be slow and in a specific location within the brain: the cerebral ventricle. The delicate procedure might pose challenges for use in people.

Young CSF restores oligodendrogenesis and memory in aged mice via Fgf17

Cerebrospinal fluid (CSF) makes up the immediate environment of brain cells, providing them with nourishing compounds. We discovered that infusing young CSF directly into aged brains improves memory function. Unbiased transcriptome analysis of the hippocampus identified oligodendrocytes to be most responsive to this rejuvenated CSF environment. We further showed that young CSF boosts oligodendrocyte progenitor cell (OPC) proliferation and differentiation in the aged hippocampus and in primary OPC cultures.

We identified serum response factor (SRF), a transcription factor that drives actin cytoskeleton rearrangement, as a mediator of OPC proliferation following exposure to young CSF. With age, SRF expression decreases in hippocampal OPCs, and the pathway is induced by acute injection with young CSF. We screened for potential SRF activators in CSF and found that fibroblast growth factor 17 (Fgf17) infusion is sufficient to induce OPC proliferation and long-term memory consolidation in aged mice while Fgf17 blockade impairs cognition in young mice. These findings demonstrate the rejuvenating power of young CSF and identify Fgf17 as a key target to restore oligodendrocyte function in the ageing brain.

The Safe, Largely Ineffective End of Biogerontology

The safe approach to develop treatments for aging is to find natural compounds and existing small molecule drugs with known safety profiles that can adjust metabolism to modestly slow aging. It doesn't aggravate those people with a conservative mindset who fear all change, even beneficial change. It is likely to be successful enough during clinical development to attract funding and give early investors a return on their investment. It is only an incremental step beyond present drug development processes, nothing radical that is likely to raise eyebrows. Thus much of the present longevity industry follows the incentives and takes the easier route.

Unfortunately, near everything derived from this philosophy of development will do very little for human life span. This end of the longevity industry will become just another arm of medical research and development that produces marginal therapies, most of which will fail in later clinical trials because the effect sizes are too small. Why is this the case? It is because researchers screen and test potential treatments in lower species, from yeast to nematode worms to mice, all of which have a much greater plasticity of life span in response to interventions that mimic the response to calorie restriction than is the case for longer-lived species such as our own. Thus most discoveries made in any unbiased search will be compounds that mimic the response to calorie restriction.

This mimicking typically means an upregulation of cellular housekeeping mechanisms such as autophagy. There is plenty of human data to show that calorie restriction, and thus the full panoply of such increased cellular maintenance, is beneficial to health. Calorie restriction doesn't, however, greatly extend life span in long-lived species such as our own: it would have been well known thousands of years ago were this the case. We can't add decades to healthy longevity via stress response upregulation of this sort.

This said, the approach of screening for novel compounds can in principle produce varieties of rejuvenation therapy that result in large improvements in late life health - such as senolytic compounds that selectively kill senescent cells. The development of senolytic therapies is a big win, and will be profoundly influential on human health once the existing low cost senolytics obtain solid clinical trial data and have percolated into common use. But this isn't the median outcome, and a discovery process that is more directed than screening for slowing of aging in mice or nematode worms is needed if we are to live meaningfully longer than our grandparents.

Antiaging agents: safe interventions to slow aging and healthy life span extension

Over the last three decades, some interventions and many preclinical studies have been found to show slowing aging and increasing the healthy lifespan of organisms from yeast, flies, rodents to nonhuman primates. The interventions are classified into two groups: lifestyle modifications and pharmacological/genetic manipulations. Some genetic pathways have been characterized to have a specific role in controlling aging and lifespan. Thus, all genes in the pathways are potential antiaging targets. Currently, many antiaging compounds target the calorie-restriction mimetic, autophagy induction, and putative enhancement of cell regeneration, epigenetic modulation of gene activity such as inhibition of histone deacetylases and DNA methyltransferases, are under development. It appears evident that the exploration of new targets for these antiaging agents based on biogerontological research provides an incredible opportunity for the healthcare and pharmaceutical industries.

Performing clinical trials to study the anti-aging potential of conventional drugs is undoubtedly a very difficult task. This is because older patients often suffer from multiple diseases and receive multiple medications simultaneously. The presence of drug-drug interactions and identified comorbidities make the evaluation of such drugs difficult, especially to assess the full range of effects produced by these drugs, whether beneficial or harmful. The lack of reliable and detectable biomarkers to assess the effectiveness of anti-aging interventions is another serious challenge.

The criteria for a potential anti-aging drug are: (1) a drug that extends the lifespan of a model organism, preferably a mammal; (2) a drug that delays or prevents some aging-related diseases in mammals; and (3) a drug that inhibits the senescence transition of cells from quiescence to senescence. The criteria may overlap. If an intervention is intended to extend lifespan, it must retard diseases associated with aging.

Many plants and fungi contain natural anti-aging products that can extend the lifespan of model organisms. These active molecules regulate the same cellular and physiological pathways that are affected by calorie restriction (CR) and exercise. Compounds that increase lifespan and healthspan mimic the effects of CR, typically by reducing insulin/IGF-1 signaling and activating autophagy and other cellular processes that increase resistance to stress.

Various strategies exist for using the anti-aging agents described here, including dietary supplements, increasing the intake of foods containing large amounts of these molecules, and/or consuming probiotics and prebiotics that raise blood levels of these molecules. Several nutrients and natural compounds have been observed to be related to increased lifespan in humans, suggesting that such strategies are feasible for slowing aging and increasing health span. Plant and fungal molecules with anti-aging properties in model organisms may also lead to the discovery and identification of new bioactive compounds for the development of improved CR mimetics to slow human aging. Except for mentioned above natural products, many other compounds have been reported to show anti-aging activity, such as acetic acid, allicin, apigenin, aspalathin, berberine, capsaicin, catalpol, celastrol, garcinol, huperzine, hydroxycitrate, inositol, naringin, piceatannol, and piperlongumine.

Biogerontology is entering a period of exciting and rapid development. It has great potential for future pharmacological interventions to slow aging. As a new era of anti-aging drug discovery dawns, the research community will need to pay special attention to the timely development of drugs that can slow the aging process, either alone or as multiple agents. Natural products provide the driving force to move forward in our quest to understand and improve the health span, just as they have always done! In regulating aging, it is hoped that these drugs will also reduce the burden of many age-related diseases.

Wanting a Longer Life Correlates with Achieving a Modestly Longer Life

Researchers here suggest that lifestyle choices mediate an observed association between desired length of life, as assessed in middle-age, and actual length of life. Those people who want to live longer will do at least something to help achieve that goal, such as avoiding obesity and lack of exercise. Or perhaps those people already suffering from a more rapid pace of aging are, on balance, disenchanted at the thought of a future decline that seems more profound - though the researchers here claim to have controlled for that contribution, given the existence of health data at the time of survey.

Desired longevity represents how strongly people esteem possible extensions of their own lifetime. The association between desired longevity and mortality risk has been reported in only one prospective study, which examined a small sample of older participants. We aimed to examine the hypothesis that desired longevity at middle-age predicted long-term survival.

In the prospective cohort study, residents aged 40-64 years were asked how long they would like to live and asked to choose one from three options: longer than, as long as, or shorter than the life expectancy. 39,902 residents were recruited to the study. Risk of all-cause mortality was significantly higher in the "shorter than" group (hazard ratio 1.12). The association was independent of sex, age, marital status, education, medical history, and health status. Regarding cause of death, mortality risk of cancer (hazard ratio 1.14) and suicide (hazard ratio 2.15) were also higher in the "shorter than" group. The unhealthy lifestyle mediated this association with all-cause mortality by 30.4%.

In conclusion, shorter desired longevity was significantly associated with an increased risk of all-cause mortality, and mortality from cancer and suicide. Lifestyle behaviors particularly mediated this association.

Senescent Cell Extracellular Vesicles in Vascular Calcification

A growing body of evidence implicates the presence of senescent cells in the development of vascular calcification. Calcification arises as cells in blood vessel walls inappropriately take on the characteristics of bone cells. Senescent cells produce inflammatory signaling that contributes to these and other detrimental changes, and much of that signaling is carried in extracellular vesicles, membrane-wrapped packages of molecules that pass between cells in tissue. The direct solution to this problem is targeted removal of senescent cells, via senolytic therapies, but that isn't stopping researchers from mapping the way in which senescent cell signaling causes dysfunction.

Vascular calcification is an irreversible pathological process associated with a loss of vascular wall function. This process occurs as a result of aging and age-related diseases, such as cardiovascular and chronic kidney diseases, and leads to comorbidities. During these age-related diseases, the endothelium accumulates senescent cells, which stimulate calcification in vascular smooth muscle cells. Currently, vascular calcification is a silent pathology, and there are no early diagnostic tools. Therefore, by the time vascular calcification is diagnosed, it is usually untreatable.

Some mediators, such as oxidative stress, inflammation, and extracellular vesicles, are inducers and promoters of vascular calcification. They play a crucial role during vascular generation and the progression of vascular calcification. Extracellular vesicles, mainly derived from injured endothelial cells that have acquired a senescent phenotype, contribute to calcification in a manner mostly dependent on two factors: (1) the number of extracellular vesicles released, and (2) their cargo. In this review, we present state-of-the-art knowledge on the composition and functions of extracellular vesicles involved in the generation and progression of vascular calcification.

Lower Physical Performance Correlates with Some Inflammation Markers

Researchers here report on a study showing that lower physical performance in old age correlates with only one of a small panel of selected blood markers of inflammation. It is expected that a greater burden of chronic inflammation will cause a more rapid decline in later life, including the loss of strength and resilience leading into frailty. Inflammation and its interaction with tissue function is sufficiently complex a topic, and sufficiently varied from individual to individual, that we might expect to see mixed results like these, however.

Maintenance of physical performance is essential for achievement of healthy aging. A few studies have explored the association between inflammatory markers and physical performance in older adults with inconclusive results. Our aim was to analyze the association of tumor necrosis factor-alpha (TNF-α), Interleukin-10 (IL-10), and C-reactive protein (CRP) with physical performance in a sample of older adults in rural settings of Mexico. Our study comprised 307 community-dwelling older men and women who participated in the third wave of the Rural Frailty Study.

In comparison with the normal physical performance group, low physical performance individuals mainly were female, older, more illiterate, more hypertensive, fewer smokers, and had higher CRP levels. The logistic model results showed a significant association between the 3rd tertile of CRP and low physical performance (odds ratio = 2.23). IL-10 and TNF-α levels did not show a significant association. The results of this study were thus mixed, with a significant association of physical performance with higher CRP levels but nonsignificant with IL-10 and TNF-α. Further studies with improved designs are needed by incorporating a broader set of inflammatory markers.

Pathogenic Viruses Have Evolved to Provoke Cellular Senescence

This open access paper presents an interesting view on the interaction between infectious viruses and cellular senescence, with a focus on neurodegenerative disease. Senescent cells are better hosts for viral replication than other cells, and thus viruses have evolved to provoke cells into becoming senescent. That in turn has the potential to produce lasting harm in an infected individual by increasing the burden of senescent cells. Chronic inflammation is an important factor in the progression of neurodegeneration, and senescent cells secrete pro-inflammatory signals. Indeed, some view tauopathies such as Alzheimer's disease as the consequence of a feedback loop between cellular senescence, inflammation, and tau aggregation: once established in some way, it will keep running independently of its origin.

A growing body of epidemiological and research data has associated neurotropic viruses with accelerated brain aging and increased risk of neurodegenerative disorders. Many viruses replicate optimally in senescent cells, as they offer a hospitable microenvironment with persistently elevated cytosolic calcium, abundant intracellular iron, and low interferon type I. As cell-cell fusion is a major driver of cellular senescence, many viruses have developed the ability to promote this phenotype by forming syncytia, multi-nucleate cells resulting from fusion.

Cell-cell fusion is associated with immunosuppression mediated by phosphatidylserine externalization that enable viruses to evade host defenses. In hosts, virus-induced immune dysfunction and premature cellular senescence may predispose to neurodegenerative disorders. This concept is supported by novel studies that found postinfectious cognitive dysfunction in several viral illnesses, including human immunodeficiency virus-1, herpes simplex virus-1, and SARS-CoV-2. Virus-induced pathological syncytia may provide a unified framework for conceptualizing neuronal cell cycle reentry, aneuploidy, somatic mosaicism, viral spreading of pathological Tau, and elimination of viable synapses and neurons by neurotoxic astrocytes and microglia.

In this narrative review, we take a closer look at cell-cell fusion and vesicular merger in the pathogenesis of neurodegenerative disorders. We present a "decentralized" information processing model that conceptualizes neurodegeneration as a systemic illness, triggered by cytoskeletal pathology. We also discuss strategies for reversing cell-cell fusion, including, TMEM16F inhibitors, calcium channel blockers, senolytics, and tubulin stabilizing agents. Finally, going beyond neurodegeneration, we examine the potential benefit of harnessing fusion as a therapeutic strategy in regenerative medicine.

Human Genetic Variants Associated with Longevity are Also Associated with Cardiovascular Health

Cardiovascular disease is responsible for a sizable fraction of human mortality, with atherosclerosis as the most important single cause of death in our species. Given this, it is perhaps not surprising to find genetic variants thought to contribute to differences in life expectancy between individuals also involved in the mechanisms of cardiovascular aging, dysfunction, and disease.

Aging is an archetypical complex process influenced by genetic and environmental factors. Genetic variants impart a gradient of effect sizes, albeit skewed toward those with small effect sizes. On one end of the spectrum are the rare monogenic premature aging syndromes, such as Hutchinson Gilford Progeria Syndrome, whereby single nucleotide changes lead to rapidly progressive premature aging. On the end of the spectrum is the complex, slowly progressive process of living to an arbitrary-defined old age, i.e., longevity.

Whereas the genetic basis of rare premature aging syndromes has been elucidated, only a small fraction of the genetic determinants of longevity and life span, time from birth to death, have been identified. The latter point to the complexity of the process and involvement of myriad of genetic and non-genetic factors and hence, the diluted effect of each determinant on longevity. The genetic discoveries point to the involvement of DNA damage and activation of the DNA damage response pathway, particularly in the premature aging syndromes. Likewise, the insulin/insulin-like growth factor 1/mTOR/FOXO pathways have emerged as major regulators of life span.

A notable fraction of the genetic variants that are associated with life span is also associated with age-related cardiovascular diseases, such as coronary artery disease and dyslipidemia, which places cardiovascular aging at the core of human life span. The clinical impact of the discoveries pertains to the identification of the pathways that are involved in life span, which might serve as targets of interventions to prevent, slow, and even possibly reverse aging.

YAP Upregulation to Reduce Astrocyte Senescence in the Aging Brain

In recent years, researchers have noted that YAP upregulation suppresses cellular senescence in a number of different cell populations. While YAP upregulation appears to have other effects, for example on cell adhesion, relevant to cancer development, the fact that it suppresses cellular senescence means that it will likely show benefits in many different age-related conditions. That doesn't mean it is any better a choice than established senolytics that clear senescent cells, of course.

Emerging evidence has shown that senescent astrocytes are involved in initiating and promoting the progression of Alzheimer's disease (AD). Senescent astrocytes exhibit expression of senescence-associated secretory phenotype (SASP). It has been reported that the number of senescent astrocytes in the frontal cortex of AD patients is significantly higher than that of non-AD adults with similar ages. Accumulation of senescent astrocytes leads to massive secretion of SASP factors, reduces amyloid-β clearance, promotes aggregation of insoluble tau. Elimination of these senescent glial cells, including astrocytes, prevents the hyperphosphorylation of tau protein, neurofibrillary tangles, and cognitive hypofunction.

Yes-associated protein (YAP), as a co-activator and multi-functional protein, is a critical effector of the Hippo pathway, and has been shown to inhibit the senescence of various types of cells. Recently, we have found that YAP is down-regulated and inactivated in senescent astrocytes, not only in cultured senescent astrocytes, but also in hippocampal astrocytes of the aging mice and AD model mice, in a Hippo pathway-dependent manner, indicating a role of YAP in astrocytic senescence.

Cyclin-dependent kinase 6 (CDK6), as a downstream molecule of YAP, is decreased in YAP knockout astrocytes in vivo and in vitro, and over-expression of CDK6 partially rejuvenates YAP knockout astrocytes, indicating that YAP inhibits astrocytic senescence through the CDK6 signaling. Moreover, activation of YAP improves the cognitive decline of AD model mice. This evidence exhibits the positive potential of the YAP-CDK6 pathway in restraining astrocytic senescence in AD.

João Pedro de Magalhães on Rejuvenation Therapies

Here find an interview with researcher João Pedro de Magalhães, nowadays involved with a new cellular reprogramming company as well as ongoing research programs in the UK. One of the more interesting parts is the commentary on rejuvenation versus slowing aging, noted below. I agree that terminology, definition, and measurement are challenges at the moment. But I would say that he is overly conservative on the point of whether or not rejuvenation can be produced in mammals, given the extensive evidence for senolytic therapies to reverse aspects of aging and the progression of specific age-related diseases.

You could argue that there are some really simple model systems where we can reverse aging. You could also argue that we can reverse aging in human cells with telomerase and cellular reprogramming with Yamanaka factors, but whether that applies to whole organs is a completely different question. The jury is still out on whether we can actually reverse aging in mammals.

I think this might be a terminology issue. If you take an obese individual, and this individual goes on a diet, they will be healthier. Their risks from various age-related diseases are going to decrease because of the diet, but that doesn't mean that this person has been rejuvenated, it just means that a lifestyle intervention improved their health.

A lot of times, you can have interventions that improve health and maybe ameliorate elements of epigenetic clocks without necessarily doing anything about the process of aging. I think we've had this problem in the field for quite a long time - that you can have interventions that increase longevity without necessarily retarding aging, just because they're healthy. Do obese individuals age faster? I wouldn't readily assume so, although some of my colleagues may disagree with me.

You can have interventions, pharmacological interventions, for instance, that extend lifespan, but don't slow down aging in humans and even in model systems. Mice mostly die of cancer, and if you have a drug that prevents cancer, the mice are going to live longer. It doesn't mean aging has been retarded, even though longevity has increased. The problem we have in the field is what do those various interventions mean? Do they really slow aging, do they reverse aging, or are they just healthy? That's why we sometimes need to be more careful about what we are claiming to have achieved.

How would you show something like aging reversal? To me, there's still a question mark on it. I think you must have some pretty strong evidence for it - functional evidence, molecular evidence. It has to be something quite substantial to prove that you've reversed aging in a mammalian organism, that you've rejuvenated a tissue. I think that would require some pretty substantial evidence which I haven't seen yet. Going back to the question, in complex models, such as mammals - no, I don't think we have really reversed aging.

T Cells Implicated in Age-Related Impairment of Nerve Regeneration

Nerve tissue is not capable of significant regeneration in mammals, but the existing limited capacity for regrowth is further diminished with age. Researchers here show that one of the major classes of T cell of the adaptive immune system causes a meaningful fraction of this diminished regenerative capacity. Prevent these T cells from engaging with injured tissue and nerve regeneration is improved as a result, at least in mice. The approach used here may form the basis for an approach to greater recovery following injury in older people, and possibly even improved maintenance of nervous system tissue in later life.

Axonal regeneration and neurological functional recovery are extremely limited in the elderly. Consequently, injuries to the nervous system are typically followed by severe and long-term disability. We hypothesized that injuries to the aged nervous system would be followed by unique molecular and cellular modifications that would contribute to aging-dependent regenerative decline. To this end, molecular and cellular signatures associated with aging and injury to the nervous system were systematically investigated by performing RNA sequencing from dorsal root ganglia (DRG) in a well-established model of sciatic nerve injury in young versus aged mice.

Initial analysis of RNA sequencing data identified that aging was mainly associated with a marked increase in T cell activation and signaling in DRG after injury. Subsequent experiments demonstrated that aging was associated with increased inflammatory cytokines in DRG both preceding and following sciatic nerve injury. Specifically, we found that lymphotoxin β was required for the phosphorylation of NF-κB that drives the expression of the chemokine CXCL13 in DRG sensory neurons. CXCL13 attracted CD8+ T cells that expressed the CXCL13 receptor CXCR5 in proximity to neurons that act as antigen-presenting cells by overexpressing major histocompatibility complex class I (MHC I) after injury. The engagement of CXCR5+CD8+ T cells with MHC I-expressing sensory neurons activated caspase 3, which leads to regenerative failure.

Neutralization of CXCL13 with monoclonal antibodies reduced the recruitment of CXCR5+CD8+ T cells to the DRG and restored the regenerative ability of sciatic sensory axons in aged mice to levels comparable to those found in young animals. CXCL13 antagonism also significantly promoted skin reinnervation and neurological recovery of sensory function.

Branched-Chain Amino Acids in the Context of Protein Restriction

There is some interest in the research community in identifying the specific triggers by which lowered intake of protein leads to beneficial shifts in metabolism and modestly slowed aging. Scientists have shown that reducing only protein intake (such as via reduced intake of methionine, an essential amino acid required for all protein synthesis) while retaining the same level of dietary calories can have similar effects to the practice of calorie restriction, an overall reduction in food intake. Thus methionine sensing is important. It isn't the only mechanism relevant to the benefits to health that result from a lower intake of macronutrients, however. Here, researchers focus on the role of branched-chain amino acids in this context, putting forward the case for branched-chain amino acid sensing to also be an important factor.

The proportion of humans suffering from age-related diseases is increasing around the world, and creative solutions are needed to promote healthy longevity. Recent work has clearly shown that a calorie is not just a calorie - and that low protein diets are associated with reduced mortality in humans and promote metabolic health and extended lifespan in rodents. Many of the benefits of protein restriction on metabolism and aging are the result of decreased consumption of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine.

Here, we discuss the emerging evidence that BCAAs are critical modulators of healthy metabolism and longevity in rodents and humans, as well as the physiological and molecular mechanisms that may drive the benefits of BCAA restriction. Our results illustrate that protein quality - the specific composition of dietary protein - may be a previously unappreciated driver of metabolic dysfunction and that reducing dietary BCAAs may be a promising new approach to delay and prevent diseases of aging.

Parabiosis Slows Aging of the Gut Microbiome in Mice

Researchers here report on an analysis of changes in the gut microbiome with age, looking at normally aged mice alongside those undergoing heterochronic parabiosis, probiotic treatment, and injection with serum from young mice. All of the interventions improved the state of the aged gut microbiome and reduced inflammation, but only some produced meaningful changes age-related frailty. The microbial populations of the gut undergo shifts with age, reductions in beneficial species and a growth in harmful species that provoke inflammation. Any intervention that improves immune function should help, given the role of the immune system in gardening the gut microbiome, as do interventions that directly change the balance of populations. In humans, the most promising approach is fecal microbiota transplantation, given that it is already an established procedure, but that doesn't stop researchers from assessing all sort of other interventions in animal studies.

The gut microbiota is associated with the health and longevity of the host. Through the aging process, age-related changes in the composition of gut microbiota have been observed, which are related to increased intestinal disorders, inflammation, cognitive decline, and increased frailty. Furthermore, remodeling of the gut microbiome has resulted in a prolonged lifespan in Drosophila melanogaster, killifish, and progeroid mice. Previous studies have clearly shown that delivery of a healthy microbiome through co-housing or fecal microbiota transplantation (FMT) enhances intestinal immunity and facilitates healthy aging.

The changes in host microbiomes still remain poorly understood. Here, we characterized both the changes in gut microbial communities and their functional potential derived from colon samples in mouse models during aging. We achieved this through four procedures including co-housing, serum injection, parabiosis, and oral administration of Akkermansia muciniphila as probiotics using bacterial 16 S rRNA sequencing and shotgun metagenomic sequencing.

These rejuvenation procedures restore age-dependent alterations in intestinal function and inflammation. Furthermore, oral administration of Akkermansia led to an improvement in the frailty index. The generated data expand the resources of the gut microbiome related to aging and rejuvenation and provide a useful dataset for research on developing therapeutic strategies to achieve healthy active aging.

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