Fight Aging! Newsletter, April 22nd 2024

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Proximate Causes of Increased Transposon Expression with Age

In today's open access paper, researchers here look at some of the proximate causes of transposable element activation, the details of the epigenetic and transcriptional issues. It is well known that transposable element activity increases with age. These are sequences capable of self-replication in the genome, the remnants of ancient retroviral infections. Transposon activity is repressed in youth, the sequences hidden from transcription machinery within compact regions of the packaged genome, or hidden inside intron sequences that are normally excluded from transcription.

Aging produces a growing dysregulation of the epigenetic control of genomic structure and gene expression, allowing transposable elements to be exposed to transcription. Further, the process of splicing by which exons and introns are assembled into RNA molecules also becomes dysregulated, allowing occasional inclusion of introns that are normally excluded in youth. The resulting activation of transposable elements becomes a source of further damage and disarray. These sequences haphazardly insert copies of themselves into the genome, breaking existing genes. They can also potentially cause other harms via their gene products, such as via provoking forms of innate immune response to viral agents.

A concerted increase in readthrough and intron retention drives transposon expression during aging and senescence

Aging and senescence are characterized by pervasive transcriptional dysfunction, including increased expression of transposons and introns. Our aim was to elucidate mechanisms behind this increased expression. Most transposons are found within genes and introns, with a large minority being close to genes. This raises the possibility that transcriptional readthrough and intron retention are responsible for age-related changes in transposon expression rather than expression of autonomous transposons.

To test this, we compiled public RNA-seq datasets from aged human fibroblasts, replicative and drug-induced senescence in human cells, and RNA-seq from aging mice and senescent mouse cells. Indeed, our reanalysis revealed a correlation between transposons expression, intron retention, and transcriptional readthrough across samples and within samples. Both intron retention and readthrough increased with aging or cellular senescence and these transcriptional defects were more pronounced in human samples as compared to those of mice.

In support of a causal connection between readthrough and transposon expression, analysis of models showing induced transcriptional readthrough confirmed that they also show elevated transposon expression. Taken together, our data suggest that elevated transposon reads during aging seen in various RNA-seq dataset are concomitant with multiple transcriptional defects. Intron retention and transcriptional readthrough are the most likely explanation for the expression of transposable elements that lack a functional promoter.

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Higher Taurine Intake in the Diet Correlates with Some Measures of Strength in Middle Age

Taurine is a amino acid mainly found in fish and meat in the diet. It is not an essential amino acid, and can be synthesized in humans. Circulating taurine levels in the bloodstream decline with age by about 50% by middle age for reasons that have yet to be determined. Studies in aged mice and non-human primates have shown modestly improved function and slowed aging following taurine supplementation. Past human studies of taurine supplementation have produced entirely unimpressive outcomes, but given that they predated present aging clocks it may be that the researchers were evaluating the wrong metrics. Taurine may act on the pace of aging through a range of different mechanisms, and it remains unclear as to which of these are more or less important.

In the context of recent studies on taurine supplementation, today's open access paper seemed interesting. The authors report on correlations between taurine intake in the normal diet with a few measures of fitness and muscle strength in middle-aged individuals. Human studies of taurine supplementation require a dose in the range of 1.5-6.0 grams per day to remove the 50% loss in circulating taurine. This supplement dose is the human equivalent extrapolated from the effective doses in mice and non-human primates. Here, dietary intake of taurine in the study participants was estimated to be ~200 milligrams per day, which is actually higher than previously reported averages, particularly for vegetarians. Given that, one might argue that taurine levels in the diet are a proxy for the influence of some other better-studied aspect of dietary choices on long-term health, such as overall protein intake.

Association of taurine intake with changes in physical fitness among community-dwelling middle-aged and older Japanese adults: an 8-year longitudinal study

Taurine has diverse valuable biological functions, including antioxidant activity and regulation of osmotic pressure. Maintaining physical fitness from middle age is important for healthy life expectancy. Although taurine administration improves muscle endurance and strength, its role in maintenance remains unclear. We aimed to clarify the longitudinal taurine intake association with fitness changes.

Participants comprised men and women aged ≥40 years who participated in the third (2002-2004; Baseline) and seventh (2010-2012; Follow-up) waves of the National Institute for Longevity Sciences-Longitudinal Study of Aging (NILS-LSA) and completed a 3-day dietary weights recording survey at baseline. A table of taurine content was prepared for 751 foods (including five food groups: Seaweed; Fish and shellfish; Meat; Eggs; and Milk and dairy products) from the Standard Tables of Food Composition in Japan (1,878 foods) 2010. Four physical fitness items (knee extension muscle strength, sit-and-reach, one-leg standing with eyes closed, and maximum walking speed) were measured at baseline and follow-up. We analyzed the association of taurine intake with physical fitness change, employing a general linear model (GLM) and trend tests for baseline taurine intake and follow-up fitness change. Adjustments included baseline variables: sex, age, height, weight, educational level, self-rated health, smoking status, depressive symptoms, and clinical history.

The estimated average daily taurine intake was 207.5 ± 145.6 mg/day at the baseline. When examining the association with the four physical fitness parameters, higher taurine intake positively increased the change in knee extension muscle strength and reduced the decline in knee extension muscle strength in the subgroup analysis of participants aged ≥65 years. No relationship was found between taurine intake and the remaining three fitness factors.

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Sea Urchins as a Model of Negligible Senescence

Species that exhibit negligible senescence tend to be long-lived, but more interestingly appear to exhibit few to none of the functional declines of degenerative aging until very late in life, quite unlike the situation for most mammals, and particularly for humans. One can argue that the most useful species that exhibit negligible senescence are those with near relative species that age more normally. The closer the relative, the more likely it is that comparing the biochemistry of the two will lead to new knowledge regarding aging. So naked mole rats versus other, less long-lived mole rats, Brandt's bat versus other shorter-lived small bats, or as in today's open access paper, the red sea urchin versus short-lived urchin species.

Whether this work on the comparative biology of aging can cost-effectively produce a basis for useful therapies in human medicine remains an open question. Research into the biochemistry of naked mole rats, probably the closest negligibly senescent species to our own species, has yet to yield a way to build useful treatments for aspects of human aging. The one experiment conducted to date involving the transfer of naked mole-rat genes into mice didn't produce the hoped-for sizable gains. It may turn out to be slow, expensive, and challenging to work towards this sort of modification of our biochemistry, as compared with the more standard approaches to medical research

Genomic signatures of exceptional longevity and negligible aging in the long-lived red sea urchin

A tremendous variety of life history strategies have evolved across the animal kingdom, including some animals that achieve remarkably long lifespans (on the order of centuries) without the physiological decline that typically accompanies aging. This phenomenon, referred to as negligible senescence, is characterized by a lack of increased mortality rate or decreased fecundity as an organism ages, in combination with maintenance of physiological function and disease resistance. Animals with extraordinary longevity and negligible senescence rely on unique mechanisms to promote long-term maintenance of tissue homeostasis and physiological function while avoiding degenerative and neoplastic diseases. Understanding these mechanisms can reveal effective strategies to achieve longevity and healthy aging.

Comparative genomics between long-lived and short-lived species is a powerful approach to understand the evolution of longevity and enables unbiased discovery of genes and pathways that regulate lifespan. This approach has been used to identify molecular signatures related to longevity and has uncovered both shared and distinct strategies to modulate aging and disease resistance. Sea urchins represent a promising group of organisms to advance our understanding of lifespan determination and healthy aging. There are approximately 1,000 extant sea urchin species that exhibit a wide range of lifespans, including species with exceptional longevity and negligible senescence.

Life history data indicates that the red sea urchin, Mesocentrotus franciscanus, is one of the Earth's longest-living animals. It is reported to live more than 100 years and shows negligible senescence as defined by indeterminate growth, life-long reproduction, and no age-associated increase in mortality rate or increased incidence of disease, including no known cases of cancer. Negligible senescence has also been reported for other sea urchin species despite a wide range of lifespans. This includes the variegated sea urchin, Lytechinus variegatus, which is reported to live 3-4 years, the painted sea urchin, Lytechinus pictus, reported to live 5-7 years, and the purple sea urchin, Strongylocentrotus purpuratus, reported to live longer than 50 years.

Studies to date, conducted within the framework of known theories of aging, have demonstrated that both short-lived and long-lived sea urchin species lack many hallmarks of aging. Sea urchins maintain telomere length, antioxidant and proteasome enzyme activities, and regenerative capacity, and exhibit little accumulation of oxidative cellular damage with age. Gene expression studies using tissues of long-lived species indicate that key cellular pathways involved in protein homeostasis, tissue regeneration, and neurological function are maintained with age. Although genomes have been assembled for several sea urchin species, including S. purpuratus, L. variegatus, and L. pictus, to date no high-quality genome has become available for the long-lived red sea urchin M. franciscanus. Here we report a chromosome-level assembly for the red sea urchin genome. Targeted analysis of this genome and comparisons between long- and short-lived species sheds light on the molecular, cellular, and systemic mechanisms that promote longevity and negligible senescence.

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Endothelial Cellular Senescence Contributes to Loss of Capillary Density

The consensus of the research community on senescent cells in old tissues is that (a) their presence causes harm, and (b) treatments based on the selective removal of such cells will be beneficial, reversing many aspects of aging and age-related disease. These cells secrete a pro-inflammatory mix of signal molecules that is disruptive to tissue structure and function when maintained over time. Cells become senescent constantly throughout life, only to be destroyed by programmed cell death or by the immune system. With advancing age, newly created senescent cells are cleared ever more slowly, however, and thus the burden of lingering senescent cells grows throughout the body.

As the authors of today's open access paper note, the presence of senescent endothelial cells in blood vessel walls is considered to be an important contributing cause of many of the age-related dysfunctions of the vasculature. One of the more consequential of these dysfunctions is the loss of capacity to grow new capillaries, leading to a decline in capillary density in tissues throughout the body. A more sparse capillary network reduces blood flow and delivery of oxygen and nutrients to cells, harming tissue function, particularly in energy-hungry tissues such as the brain and muscles. To the extent that senolytic therapies to clear senescent cells can reverse this particular aspect of aging, we should all be in favor of senolytic therapies.

Endothelial Senescence: From Macro- to Micro-Vasculature and Its Implications on Cardiovascular Health

Cellular senescence is originally defined as the irreversible loss of proliferative potential in somatic cells, which enter a viable and metabolically active state of permanent growth arrest that is distinct from quiescence and terminal differentiation. Accumulation of senescent cells contributes to age-related tissue degeneration by developing a complex senescence-associated secretory phenotype (SASP). By secreting a plethora of factors, including pro-inflammatory cytokines, chemokines, growth modulators, matrix metalloproteinases, and compromised extracellular vesicles which represent senescence-associated phenotype, senescent cells reprogram the surrounding microenvironment and cause tissue damage, thus promoting ageing and the development of age-associated diseases.

Intervention experiments have proven that senescent cell accumulation is an important driver of age-associated functional decline, multi-morbidity, and mortality, while systemic clearance of senescent cells delays ageing and extend lifespan. Therapeutically targeting cellular senescence, known as senotherapy, to eliminate senescent cells or induce senolysis, represents a rapidly growing and promising strategy for the prevention and/or treatment of ageing-related diseases. Targeting senescent cells can improve both health-span and life-span in mice.

Endothelial cells line at the most inner layer of blood vessels. They act to control hemostasis, arterial tone/reactivity, wound healing, tissue oxygen, and nutrient supply. With age, endothelial cells become senescent, characterized by reduced regeneration capacity, inflammation, and abnormal secretory profile. Endothelial senescence represents one of the earliest features of arterial ageing and contributes to many age-related diseases.

Compared to those in arteries and veins, endothelial cells of the microcirculation exhibit a greater extent of heterogeneity. Microcirculatory endothelial senescence leads to a declined capillary density, reduced angiogenic potentials, decreased blood flow, impaired barrier properties, and hypoperfusion in a tissue or organ-dependent manner. The heterogeneous phenotypes of microvascular endothelial cells in a particular vascular bed and across different tissues remain largely unknown. Accordingly, the mechanisms underlying macro- and micro-vascular endothelial senescence vary in different pathophysiological conditions, thus offering specific targets for therapeutic development of senolytic drugs.

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Parkinson's Disease in the SENS View of Damage Repair

The Strategies for Engineered Negligible Senescence (SENS) is a view of aging as accumulated damage. Drawing from the extensive scientific literature on aging, the originators of SENS created an outline of the forms of cell and tissue damage that are fundamental causes of aging, in that they occur as a natural side-effect of the normal operation of our cellular biochemistry. So we might consider the loss of vital cells due to declining stem cell function, mutations to nuclear DNA and mitochondrial DNA, cross-linking of vital molecules in the extracellular matrix, accumulated metabolic waste in long-lived cells, generation of amyloids from misfolded proteins, and the accumulation of senescent cells, for example.

These forms of damage accumulate to cause other, downstream forms of damage and dysfunction that, collectively, give rise to degenerative aging and age-related mortality. Aging is a very complex in its details, but only because cellular biochemistry is very complex. Complex systems malfunction in response to damage in complex ways, but the root causes of aging, the forms of damage noted above, are much less complex and thus much easier to visualize, describe, and intervene in.

Because SENS specifies the forms of damage in some detail, it also describes what needs to be done in order to reverse the progression of aging: repair the damage. Removing damage that is disruptive to cell and tissue function allows cell and tissues to improve their function and restore a more youthful environment. That said, there are all too few examples in which an author picks a specific age-related disease and breaks down its pathology into SENS terms. Today's article does that for Parkinson's disease, and notes that multiple different forms of damage are significant in driving its progress, is the case for near all age-related conditions. Any one narrowly focused rejuvenation therapy that addresses only one form of damage will improve matters only somewhat. It won't solve the whole problem. The SENS view of medical development inevitably leads to the development and use of many different therapies in combination.

Repairing the Damage to Shake Off Parkinson's

While most aging people don't suffer clinically-diagnosable Parkinson's, it's unsettlingly common to be afflicted by what are called "mild parkinsonian signs" or "Parkinsonism:" about one in six people ages 65 to 74, nearly one-third of those 75 to 84, and over half of those 85 and older. In addition to having to live with less severe versions of many common symptoms of Parkinson's itself (see below), people with Parkinsonism are at roughly double the risk of death in any given year as people the same age without it. Scientists have made exciting progress against Alzheimer's disease recently, with two new AmyloSENS therapies having proven themselves in clinical trials and more benefits and insights continuing to roll in. So it's a good time to take stock of where we are with cellular and molecular aging damage-repair therapies that would prevent and reverse the second most common neurodegenerative aging disorder.

The most visible symptoms of Parkinson's, and the ones on whose basis people are diagnosed with the "disease," are what are called the "motor symptoms." These symptoms result from the progressive loss of - and damage to - a specific population of neurons located in an area of the brain called the substantia nigra pars compacta (SNc). There is enough built-in redundancy in the SNc that we continue losing these "dopaminergic" neurons for decades without any obvious problems. But once our supply of these neurons dwindles to beneath the "threshold of pathology," we can no longer make these fine adjustments to the movement-control signals, and the motor symptoms of Parkinson's subvert the movement of our faces, hands, and bodies. The rejuvenation biotechnology solution to this problem is to repair the damage by replacing the lost neurons. The good news is that scientists have been working on dopaminergic neuron transplantation for longer than any other kind of true cell replacement (RepleniSENS) therapy. BlueRock Therapeutics uses proprietary bioprocessing to create stable master cell banks of what they call "universal iPSCs," which they have found to be compatible with the immune system of any patient. BlueRock scientists then differentiate these cells into dopaminergic neurons for transplant into the brains of people with Parkinson's. They recently reported positive safety results from a Phase I trial.

Our brains accumulate aggregates comprised of the protein alpha-synuclein (AS) as we age, both inside and between our neurons. People suffering from diagnosed Parkinson's and closely-related neurological aging disorders bear especially high burdens of these aggregates. Fortunately, researchers are currently running clinical trials to test numerous AmyloSENS therapies to clear AS aggregates located outside of cells. Most of these trials are in Phase II. Unfortunately, no one has yet developed LysoSENS therapies to target AS aggregates inside the cell, and it's these intracellular AS aggregates that likely inflict the greatest harm. The main reason for this seemingly backward prioritization is that it's not obvious how you would target AS aggregates inside cells. Fortunately, there is a potential path forward. Several years ago, researchers reported on a novel way to smuggle antibodies into cells intact. If researchers could instead send in catalytic antibodies (catabodies) that would chop pathological aggregates into tiny pieces inside the cell. SENS Research Foundation scientists are working to develop this intracellular aggregate-targeting catabody approach right now.

As we age, a small percentage of long-lived cells that don't divide (such as neurons and muscle cells) get completely taken over by mitochondria that have suffered the loss of huge chunks of their DNA. And of all the cells in the body, the cell type that is most susceptible to this hostile takeover is the critical population of dopaminergic neurons whose loss is central to Parkinson's. It's not clear what the connection is between these DNA deletion-bearing mitochondria and the loss of dopaminergic neurons with age, but it seems safe to assume that even if they don't kill their host neurons, deletion-bearing mitochondria sweeping across the cell leads to an energetic brownout that makes any surviving neurons less effective. The MitoSENS lab at SENS Research Foundation is working to develop three different platform technologies (including the original MitoSENS strategy of allotopic expression) to prevent, replace, or bypass mitochondrial DNA mutations.

Astrocytes are a kind of cellular butler for brain neurons, serving them energy sources and keeping their environment orderly so they can do their job. But like many cell types, astrocytes can turn senescent with age in response to many kinds of stress and injury. Researchers have reported that the brains of people with Parkinson's have a higher burden of senescent astrocytes than do people the same age who are free of the disease. To see if senescent astrocytes were really driving Parkinson's-like degeneration in living mammals, the researchers conducted an experiment using mice in whom they could destroy senescent cells at will. Scientists had engineered these mice with ApoptoSENS "suicide genes" that would detonate in senescent cells anytime the scientists "pulled the trigger" by treating them with a drug that activates the genetic system. They treated one group of these Parkinson's-like mice with the drug that would activate the ApoptoSENS "suicide genes" in any senescent cells they might harbor, while leaving another group of Parkinson's mice untreated for comparison. The control Parkinson's mice suffered a massive loss of dopaminergic neurons, developed movement problems that stand in for the symptoms of Parkinson's, and lost much of their ability to generate new neurons elsewhere in the brain. But much of this damage and dysfunction was prevented when researchers gave Parkinson's mice an ApoptoSENS treatment.

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Herpes Simplex Infection Correlates with Amyloid Burden in the Aging Brain

There is a continuing debate over the degree to which Alzheimer's is driven by persistent infection in brain tissue, such as by varieties of herpesvirus. Amyloid-β is an antimicrobial peptide, a part of the innate immune response, and one could argue that persistently raised expression of amyloid-β will increase misfolding and generation of the aggregates that drive pathology in the early stages of Alzheimer's disease, at least under the amyloid cascade hypothesis. The data is not all convincing, however, which suggests that perhaps there are other factors involved - that multiple viruses interact in some people, for example, or a pathological interaction between viral infection and some other aspect of brain aging only occurs in some people. It remains to be seen as to where this line of research will lead, but even now it seems a good cost-benefit decision to be using antiviral drugs in later life.

Mounting data suggests that herpes simplex virus type 1 (HSV-1) is involved in the pathogenesis of Alzheimer's disease (AD), possibly instigating amyloid-beta (Aβ) accumulation decades before the onset of clinical symptoms. However, human in vivo evidence linking HSV-1 infection to AD pathology is lacking in normal aging. To shed light into this question, serum anti-HSV IgG levels were correlated with measures of Aβ deposits and blood markers of neurodegeneration in cognitively normal older adults. Additionally, we investigated whether associations between anti-HSV IgG and AD markers were more evident in APOE4 carriers.

We showed that increased anti-HSV IgG levels are associated with higher Aβ load in fronto-temporal regions of cognitively normal older adults. Remarkably, these cortical regions exhibited abnormal patterns of resting state-functional connectivity (rs-FC) only in those individuals showing the highest levels of anti-HSV IgG. We further found that positive relationships between anti-HSV IgG levels and Aβ load, particularly in the anterior cingulate cortex, are moderated by the APOE4 genotype, the strongest genetic risk factor for AD. Importantly, anti-HSV IgG levels were unrelated to either subclinical cognitive deficits or to blood markers of neurodegeneration.

These results suggest that HSV infection is selectively related to cortical Aβ deposition in normal aging, supporting the inclusion of cognitively normal older adults in prospective trials of antimicrobial therapy aimed at decreasing the AD risk in the aging population.

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Mesenchymal Stem Cell Therapy Produces Thymus Regrowth in Old Non-Human Primates

Thymocytes generated in the bone marrow migrate to the thymus, near the heart, where they mature into T cells of the adaptive immune system. Unfortunately, the thymus atrophies with age. Most people have little active thymus tissue left by the time they are in their 50s. Absent a robust supply of new T cells, the adaptive immune system becomes ever more made up of malfunctioning, senescent, and other problematic cells, lacking the naive T cells needed to respond to new threats. Regeneration of the thymus is thus an important goal. There are some indications that the thymus is more plastic than thought, given that mild calorie restriction in humans produced some gains. Additionally, a growth hormone based therapy has shown some signs of improvement in small human trials. Here, researchers show that stem cell transplantation can produce thymic regrowth in old non-human primates, making this an option that should be evaluated in human patients.

A decrease in the number and activity of thymic epithelial cells (TECs) is an important factor in thymic degeneration. Mesenchymal stem cells (MSCs) treating thymic ageing is a promising strategy. Aged rhesus monkeys were treated with MSCs to establish a thymic senescence model, and hematoxylin-eosin (HE) staining, immunofluorescence staining, and ELISA were performed to observe the structure and function of the thymus. TEC aging model and MSCs co-culture system were established to detect DNA methylation modification and transcriptomic changes, correlation analysis between transcription factor methylation and mRNA expression, and q-PCR, immunofluorescence staining, and Western blot were used to identified key genes.

MSCs improved the structure and function of the thymus in elderly macaque monkeys; reduced the expression levels of β-Gal, P16, and P21; and increased the activity of aging TECs. There were 501 genes with increased methylation in the promoter region in the treated group compared with the untreated group, among which 23 genes were involved in the negative regulation of cell growth, proliferation, and apoptosis, while 591 genes had decreased methylation, among which 37 genes were associated with promoting cell growth and proliferation and inhibiting apoptosis. Furthermore, 66 genes showed a negative correlation between promoter methylation levels and gene transcription; specifically, PDE5A, DUOX2, LAMP1, and SVIL were downregulated with increased methylation, inhibiting growth and development, while POLR3G, PGF, CHTF18, KRT17, FOXJ1, NGF, DYRK3, LRP8, CDT1, PRELID1, F2R, KNTC1, and TRIM3 were upregulated with decreased methylation, promoting cell growth.

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Considering Cellular Senescence in Macrophages

Cells become senescent in response to damage, a toxic environment, the signaling of nearby senescent cells, or, most commonly, because they reach the Hayflick limit on replication. Senescent cells cease replication and begin to secrete pro-inflammatory signals, attracting the attention of the immune system. With advancing age he aged immune system becomes less able to clear senescent cells in a timely manner, leading to a growing, permanent presence of senescent cells in tissues. Some of these senescent cells are themselves immune cells. Given the importance of the immune system to tissue maintenance and regeneration, particularly tissue residence innate immune cells such as macrophages, it should be no surprise to find that senescence in these cells is viewed as contributing to degenerative aging.

Macrophage senescence, manifested by the special form of durable cell cycle arrest and chronic low-grade inflammation like senescence-associated secretory phenotype, has long been considered harmful. As the first-responder to the pathogens and damage in the immune response, macrophages play a vital role in the function of phagocytosis and polarization towards different situations to mediate the inflammation inside individuals. Senescent macrophages are usually featured with an unbalanced polarization state, compromised phagocytosis, impaired migration, and damaged autophagy. Due to the abnormal accumulation and the aberrant functions of senescent macrophages, aged people tend to be unhealthy or with acerbated diseases.

Senescent macrophages play various functions in different diseases or organs which indicates that treatments should be specialized for the distinctive characteristics of senescent macrophages. In the cognitive decline, senescent macrophages turn to behave abnormally in phagocytosis for the dampened scavenging of abnormal unfolded proteins in the central nervous system. The imbalanced polarization state in senescent macrophages also contributes to the development of malignant cancers. More senescent macrophages tend to the M2 phenotype promoting tumor cells proliferating and counteract against cytotoxic T lymphocytes.

Contrarily, in ovarian tissue, senescent macrophages turn to the M1 phenotype with a higher level of iNOS which causes ovarian aging. Secretions of senescent macrophages are also in close relationship with some organ disorders. Grancalcin produced by senescent macrophages would exacerbate skeletal aging for the impaired balance between osteogenesis and adipogenesis of bone marrow stroma cells. Additionally, metabolic disturbances like chaotic cholesterol levels in senescent macrophages cause age-related macular degeneration for their proangiogenic function.

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Inducing Low Body Temperature via Torpor Slows Aging in Mice

Past evidence has suggested that the lowered body temperature characteristic of calorie restriction is important to the slowed aging that results in short-lived mammals. One might compare that to the strong evidence for upregulated autophagy to be the driving factor in slowed aging produced by the practice of calorie restriction. Researchers here conduct a similar study, inducing a reduction in metabolic rate, dietary intake, and body temperature in mice via activation of a specific brain region. As in past research, the resulting slowed aging was shown to be driven by that lowered body temperature rather than any of the other effects of this intervention.

Torpor and hibernation are extreme physiological adaptations of homeotherms associated with pro-longevity effects. Yet the underlying mechanisms of how torpor affects aging, and whether hypothermic and hypometabolic states can be induced to slow aging and increase health span, remain unknown. We demonstrate that the activity of a spatially defined neuronal population in the anterior and ventral portions of the medial and lateral preoptic area (avMLPA), which has previously been identified as a torpor-regulating brain region, is sufficient to induce a torpor like state (TLS) in mice.

Prolonged induction of TLS slows epigenetic aging across multiple tissues and improves health span. We isolate the effects of decreased metabolic rate, long-term caloric restriction, and decreased core body temperature (Tb) on blood epigenetic aging and find that the pro-longevity effect of torpor-like states is mediated by decreased Tb. Taken together, our findings provide novel mechanistic insight into the pro-longevity effects of torpor and hibernation and support the growing body of evidence that Tb is an important mediator of aging processes.

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Bacterial Peptides Improve Mitochondrial Function in Intestinal Tissues

Many compounds are now known to have some positive influence on mitochondrial function. The biochemistry is complex and incompletely understood. Even in the well-studied cases, there are hypotheses regarding the mechanism of action, but little certainty. In general, improvement of the quality control mechanism of mitophagy appears to be a necessary factor in the improvement of mitochondrial function in old tissues, but that appears to happen as the result of many different types of intervention. Here, researchers note that a class of bacterial peptides originating from the gut microbiome appear to improve mitochondrial function in intestinal tissue. This may be the basis for yet another type of treatment or supplement to modestly improve mitochondrial function. Those developed to date struggle to improve on the effects of exercise, however.

Mitochondrial dysfunction critically contributes to many major human diseases. The impact of specific gut microbial metabolites on mitochondrial functions of animals and the underlying mechanisms remain to be uncovered. Here, we report a profound role of bacterial peptidoglycan muropeptides in promoting mitochondrial functions in multiple mammalian models. Muropeptide addition to human intestinal epithelial cells (IECs) leads to increased oxidative respiration and ATP production and decreased oxidative stress. Strikingly, muropeptide treatment can recover mitochondrial structure and functions and inhibits several pathological phenotypes of fibroblast cells derived from patients with mitochondrial disease.

In mice, muropeptides accumulate in mitochondria of IECs and promote small intestinal homeostasis and nutrient absorption by modulating energy metabolism. Muropeptides directly bind to ATP synthase, stabilize the complex, and promote its enzymatic activity in vitro, supporting the hypothesis that muropeptides promote mitochondria homeostasis at least in part by acting as ATP synthase agonists. This study reveals a potential treatment for human mitochondrial diseases.

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A Population Study Correlates Air Pollution with Faster Cognitive Aging

A number of large epidemiological studies provide evidence for long-term exposure to greater levels of air pollution to accelerate the onset and progression of age-related disease. A few of these manage to control for the tendency for wealthier people to avoid living in areas with higher particulate air pollution, and the correlation with worse health remains. Mechanistically, it is thought that particulates provoke greater chronic inflammation via their interaction with lung and other tissues, and this in turn contributes to the cell and tissue dysfunction that leads to age-related disease.

The present study assessed cognitive test performance in English older adults in relation to long-term air pollution exposure at the residential address. The follow-up period of 15 years and the large number of repeated measurements make the present study unique in terms of design and data availability. Increasing exposure to NO2, PM10 and PM2.5 was consistently found to be associated with decreased memory and executive function test performance, whilst ozone showed the opposite effect. The results remained similar in the analysis including residents of London only, for whom exposure to NO2 and PM was higher. As an illustrative example, the decline in memory and executive function scores per interquartile range (IQR) increase in long-term NO2 exposure was found equivalent to ageing by about 1.5 and 4 years respectively.

In order to fully elucidate the potentially adverse cognitive effects of air pollution, further study into the underlying biological pathways and mechanisms through which air pollution may contribute to cognitive decline is required alongside the expanding epidemiological work. Translocation of inhaled particles from the lung to the brain via the bloodstream provides one possible pathway through which particulate matter may affect cognition, as well as inhalation through the nose and transportation to the olfactory bulb via olfactory nerves. Evidence for such pathways is currently limited and further experimental studies are required.

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An Interview with Reason of Repair Biotechnologies on Reversal of Atherosclerosis

As some of you may know, I co-founded Repair Biotechnologies with Bill Cherman. The company is presently on the development of a gene therapy approach now demonstrated to rapidly reverse atherosclerosis in mice, the condition in which fatty plaques grow to narrow blood vessels and weaken blood vessel walls. One of the possible approaches to treating aging as a medical condition is to take the list of causes of human mortality, start at the top, and work down. Atherosclerosis is the single largest cause of death in our species, through the rupture of unstable atherosclerotic plaque leading to heart attack or stroke. The burden of established plaque correlates with mortality risk, but repeatable, sizable reversal of plaque in patients cannot be achieved by the current approaches to treatment that are focused on lifestyle factors and LDL-cholesterol level in the bloodstream.

To date, we have used our Cholesterol Degrading Platform (CDP) to demonstrate rapid and profound reversal of disease in mouse models of (a) metabolic dysfunction-associated steatohepatitis (MASH), a progression of fatty liver towards liver failure that is characterized by fibrosis and loss of liver function, (b) atherosclerosis, the buildup of fatty plaques in blood vessel walls, leading to cardiovascular disease and stroke, and (c) homozygous familial hypercholesterolemia (HoFH), an inherited condition involving loss-of-function mutations in low-density lipoprotein receptors (LDLR) that causes high blood cholesterol and greatly accelerated atherosclerosis.

These three conditions are characterized by being largely irreversible under the present standards of care. While slowing the progression of disease is sometimes possible, few patients have been shown to achieve any meaningful reversal of established liver fibrosis or arterial atherosclerotic plaque, and the methods used to treat those patients are not consistently effective in other patients.

In each case, 6 to 8 weeks of once-weekly injections of CDP therapy produced sizable improvements in blood chemistry, including reductions in alanine aminotransferase (ALT), a measure of liver cell death and stress, and in histological assessments of disease. In MASH model mice, a 52% reduction in liver fibrosis was observed versus untreated controls. In the ApoE-knockout mouse model of atherosclerosis, plaque lipids were reduced by 19% while plaque collagen increased by 23% versus controls, a dramatic stabilization of unstable plaques at risk of rupture. In the LDLR-knockout mouse model of HoFH, plaque cross-sectional area decreased by 17% and mouse treadmill performance improved by 60% versus controls, a considerable improvement in cardiovascular function.

To compare this with other present efforts, the drug, resmetirom (Madrigal Pharmaceuticals), recently approved by the FDA for the treatment of MASH, has no effect on fibrosis in mice over 8 weeks of treatment. In the MAESTRO human trial in patients with comparatively mild MASH, the treated groups saw only a 25% reduction in fibrosis compared to 14% in the placebo group after 52 weeks of treatment. In the case of atherosclerosis, large clinical trials have shown that long-term treatment with statins or other low-density lipoprotein (LDL)-lowering technologies such as PCSK9 inhibitors fails to produce a reduction in atherosclerotic plaque volume of more than a few percentage points. Our CDP therapy far outperforms these approaches to treatment.

Perhaps the most interesting outcome is that we have demonstrated that a localized excess of free cholesterol is indeed a major factor in many conditions, age-related and obesity-related. It had been theorized that this was the case for liver diseases such as MASH, but lacking a technology that selectively cleared only free cholesterol, this had to remain only a compelling theory. Armed with that selective clearance technology, our results have now convincingly demonstrated that free cholesterol toxicity is a major, important target for many conditions.

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Gut Microbiome Composition Correlates with Longevity in Rabbits

The balance of microbial populations making up the gut microbiome is different from individual to individual, and changes with age in detrimental ways. Pro-inflammatory microbes, as well as those that create otherwise harmful metabolites, expand in number at the expense of microbial populations that produce beneficial metabolites. Evidence strongly suggests that both variations between individuals and age-related changes in the gut microbiome can contribute to age-related disease and mortality. Here, for example, a study in rabbits shows that specific differences in the gut microbiome correlate well with observed length of life.

Longevity and resilience are two fundamental traits for more sustainable livestock production. These traits are closely related, as resilient animals tend to have longer lifespans. An interesting criterion for increasing longevity in rabbits could be based on the information provided by its gut microbiome. The gut microbiome is essential for regulating health and plays crucial roles in the development of the immune system.

The aim of this research was to investigate if animals with different longevities have different microbial profiles. We sequenced the 16S rRNA gene from soft faeces from 95 does. First, we compared two maternal rabbit lines with different longevities; a standard longevity maternal line (A) and a maternal line (LP) that was founded based on longevity criteria: females with a minimum of 25 parities with an average prolificacy per parity of 9 or more. Second, we compared the gut microbiota of two groups of animals from line LP with different longevities: females that died/were culled with two parities or less (LLP) and females with more than 15 parities (HLP).

Differences in alpha diversity and beta diversity were observed between lines A and LP, and analysis showed a high prediction accuracy (more than 91%) of classification of animals to line A versus LP. Interestingly, some of the most important microbial taxa identified were common to both comparisons (Akkermansia, Christensenellaceae R-7, Uncultured Eubacteriaceae, among others) and have been reported to be related to resilience and longevity.

In summary, our results indicate that the first parity gut microbiome profile differs between the two rabbit maternal lines (A and LP) and, to a lesser extent, between animals of line LP with different longevities (LLP and HLP). Several genera were able to discriminate animals from the two lines and animals with different longevities, which shows that the gut microbiome could be used as a predictive factor for longevity, or as a selection criterion for these traits.

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MKP1 as a Target for Idiopathic Pulmonary Fibrosis

The causes of idiopathic pulmonary fibrosis remain somewhat unclear, which is often the case for conditions in which treatments struggle to achieve more than a slowed progression. There is evidence for cellular senescence to drive the progression of fibrosis, but most research remains focused on the molecular biochemistry of fibroblasts, the cells responsible for building the collagen deposits characteristic of fibrotic tissue.

The process by which lung injury either leads to healing or fibrosis relies in part on what happens to a cell called a fibroblast, which forms connective tissue. During injury or illness, fibroblasts are activated, becoming myofibroblasts that form scar tissue by secreting collagen. When the job is done, these fibroblasts must be deactivated, or de-differentiated, to go back to their quiet state or undergo programmed cell death and be cleared.

This is the major distinction between normal wound healing and fibrosis - the persistence of activated myofibroblasts. That deactivation is controlled by molecular brakes. The study examined one of these brakes, called MKP1 - which researchers found was expressed at lower levels in fibroblasts from patients with idiopathic pulmonary fibrosis. By genetically eliminating MKP1 in fibroblasts of mice after establishing lung injury, the researchers saw that fibrosis continued uncontrolled.

"Instead of at day 63, seeing that nice resolution, you still see fibrosis. We argued by contradiction: when you knock out this brake, fibrosis that would otherwise naturally disappear, persists and therefore MKP1 is necessary for spontaneous resolution of fibrosis. We demonstrated that neither of the FDA approved drugs for lung fibrosis, pirfenidone and nintedanib, are able to turn off myofibroblasts. That's totally in keeping with the fact that they do slow the progression, but they don't halt or reverse disease."

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Bis(monoacylglycero)phosphates Accumulate in Aged Tissues

Lipid metabolism is changed and disrupted with advancing age, as is the case for all complex mechanisms in the body. There are a great many different lipids present in the body; even the list of classes of lipid is a long one. Finding specific changes that relate to aging can be interesting, but the challenge lie in better understanding how those changes come about, and whether they causes significant harm to tissues. Many age-related changes in molecular biochemistry are far downstream of the important causes of aging and do not cause much further disruption in and of themselves.

In recent years, laboratory research has shown that we may be able to counteract age-related diseases by intervening in the fundamental processes that lead to ageing. Although science has increasingly mapped out how metabolism changes during aging, large parts remained uncharted. "We wanted to add a new chapter to the atlas. Lipids are an important part of our diet, and crucial for the functioning of our body cells. Specific lipids make up the membrane of cells, which ensures that the inside and outside remain separate."

In order to add this new chapter, the research team investigated how the composition of fats changes in mice. They looked at ten different tissues, including muscles, kidneys, liver and heart. It was noticed that one type of lipid, the bis(monoacylglycero)phosphates (or BMPs), were elevated in all tissues from the older animals. Suggesting an accumulation of these lipids during aging. They then investigated whether this also happens in humans. Although it was not possible to obtain as many different tissues, the accumulation of BMP was also visible in muscle biopsies of older people. Finally, they then completed more muscle biopsies from people before and after a healthy intervention that included one hour of exercise a day and saw the level of BMPs decreased in the active participants.

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