Fight Aging! Newsletter, March 11th 2024

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Human Data on Epigenetic Age Following Senolytic Treatment

In today's open access paper, researchers report on the results of a small clinical trial of senolytic treatments to clear senescent cells in human patients. The treatment produced a short term increase in epigenetic age as measured via immune cells in a blood sample, not the hoped-for result. Bear in mind that one of the senolytic treatments used in this small study, dasatinib and quercetin, has been shown to clear senescent cells in at least some tissues in earlier human studies. Given the well-established role of lingering senescent cells in degenerative aging, at least in mice, why the treatment produced no lasting decrease in epigenetic age in this study is an interesting question.

Firstly, it is entirely possible that current epigenetic clocks are insensitive to the contribution of senescent cells to degenerative aging. Some clocks have demonstrated insensitivity to other factors in the past, such as physical fitness or chronic inflammation. The results may also reflect changes in immune cell population sizes and behaviors rather than anything more significant about aging; this is ever the challenge when looking at epigenetic age in blood samples. It is also possible that the limited data on whether established senolytic treatments clear senescent cells in humans as well as they do in mice is in error, and we'll have to wait for different therapies, those currently under development, to reach clinical trials in order to learn more.

Lastly, it is possible that many of the patients used in the study may not have been old enough to have sizable burdens of senescent cells. With an average age of ~60 and lowest age of 40-something in the study group, it is reasonably to think that something like half of the participants may not have exhibited a sizable burden of senescent cells. Research is never simple!

Exploring the effects of Dasatinib, Quercetin, and Fisetin on DNA methylation clocks: a longitudinal study on senolytic interventions

Given the potential role of senescence in aging, senolytic drugs have emerged as promising candidates for extending lifespan. Some initially identified senolytics were Dasatinib, Quercetin, and Fisetin. These molecules were drugs or natural products already used for other indications in humans, including anti-cancer therapies.

Dasatinib is a tyrosine kinase inhibitor approved by the FDA to treat myeloid leukemia. Quercetin is a flavonoid compound that induces apoptosis in senescent endothelial cells. Combined treatment with Dasatinib and Quercetin (DQ) has been demonstrated to decrease senescent cell burden in humans in multiple tissues; improve pulmonary and physical function along with survival in mice while lessening their age-dependent intervertebral disc degeneration; and reduce senescence and inflammatory markers in non-human primates. In human studies, patients with idiopathic pulmonary fibrosis, a senescence associated disease, improved 6-minute walk distance, walking speed, chair rise ability and short physical performance battery after 9 doses of oral DQ over 3 weeks.

Fisetin is another flavonoid compound that has gained recognition for its anti-proliferative, anti-inflammatory, and anti-metastatic properties. Fisetin has the potential to reduce senescence markers in multiple tissues in murine and human subjects. Administration of Fisetin to old mice restored tissue homeostasis, reduced age-related pathology, and extended median and maximum lifespan. Notably, a comparative study has highlighted Fisetin as the safest and most potent natural senolytic among the tested compounds.

This study aimed to assess the effects of Dasatinib and Quercetin (DQ) senolytic treatment on DNA methylation (DNAm), epigenetic age, and immune cell subsets. In a Phase I pilot study, 19 participants received DQ for 6 months, with DNAm measured at baseline, 3 months, and 6 months. The age range of these individuals that were considered in the first study analyses were between 43.0 and 86.6.

Significant increases in epigenetic age acceleration were observed in first-generation epigenetic clocks and mitotic clocks at 3 and 6 months, along with a notable decrease in telomere length. However, no significant differences were observed in second and third-generation clocks. Building upon these findings, a subsequent investigation evaluated the combination of DQ with Fisetin (DQF), a well-known antioxidant and antiaging senolytic molecule. After one year, 19 participants (including 10 from the initial study) received DQF for 6 months, with DNAm assessed at baseline and 6 months. Remarkably, the addition of Fisetin to the treatment resulted in non-significant increases in epigenetic age acceleration, suggesting a potential mitigating effect of Fisetin on the impact of DQ on epigenetic aging.

Furthermore, our analyses unveiled notable differences in immune cell proportions between the DQ and DQF treatment groups, providing a biological basis for the divergent patterns observed in the evolution of epigenetic clocks. These findings warrant further research to validate and comprehensively understand the implications of these combined interventions.

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Catalase to Reduce Mitochondrial Oxidative Stress Does Not Reduce Cellular Senescence

Every cell contains hundreds of mitochondria, the descendants of ancient symbiotic bacteria now integrated into the cell. Mitochondria generate oxidative molecules as a consequence of the processes that generate the chemical energy store molecule adenosine triphosphate (ATP), used to power the cell. Those oxidative molecules cause damage, near all rapidly repaired. They also serve as signals, such as in the beneficial response to exercise. With aging, however, mitochondrial function becomes impaired and the degree of oxidative stress generated by the operation of mitochondria becomes harmful.

Researchers have in the past produced modestly extended life in short-lived model organisms by overexpression of natural mitochondrial antioxidants such as catalase or via use of engineered antioxidant molecules targeted to mitochondria like SkQ1. This approach of dampening excessive mitochondrial generation of oxidative molecules seems generally beneficial, but the effects on life span in mice are small in more recent, more rigorously conducted studies. Today's open access paper provides a further data point, in that the scientists involved demonstrate that catalase upregulation fails to reduce the burden of cellular senescence in old mice. As they point out, this somewhat complicates present thinking on the interactions between age-related mitochondrial dysfunction and burden of cellular senescence.

Mitochondria-Targeted Catalase Does Not Suppress Development of Cellular Senescence during Aging

The loss of mitochondrial function is a potentially important driver of aging and can limit the life and health span of mammals. One aspect of this loss is an increase in mitochondrial reactive oxygen species (ROS) as these organelles are a major site for ROS generation. Murine knockouts of antioxidant enzymes such as superoxide dismutases 1 and 2 (SOD1 and SOD2) and catalase (CAT) are short-lived, indicating that cellular antioxidant defenses are required for normal life and health spans. Furthermore, increasing antioxidant proteins or treatment with antioxidants can extend the life span of invertebrate models. Despite these data, the overexpression of most antioxidant enzymes does not extend the life span of mice, suggesting that antioxidant defenses in these animals are already sufficient for geroprotection under unstressed conditions.

A notable exception to this occurs in the case of a mitochondrially targeted catalase (mCAT) transgene. In this model, catalase-which converts hydrogen peroxide into O2 and water-specifically targets mitochondria, providing these organelles with an added layer of protection from a common source of ROS-mediated damage. These mice live 10-20% longer than wild-type (WT) mice and are protected from the age-related loss of mitochondrial function, but it remains unclear if mCAT can attenuate the development of other aspects of aging, such as cellular senescence.

Cellular senescence is a stress or damage response characterized by a proliferative growth arrest accompanied by the release of various cytokines, chemokines, growth factors, proteases, oxylipins, and other signaling molecules collectively known as the senescence-associated secretory phenotype (SASP). Senescent cells have been linked to a number of age-related diseases and can limit both life and health spans, as the elimination of these cells protects against the development of several age-related pathologies. Importantly, mitochondrial dysfunction and ROS can drive cellular senescence in culture, as well as in the skin and adipose tissue of mice.

We previously demonstrated that mitochondrial dysfunction can result in a senescent phenotype that lacks multiple proinflammatory features found in the SASP. This mitochondrial-dysfunction-associated senescence (MiDAS) occurs in response to alterations in the cytosolic NAD+/NADH ratio, regardless of ROS status, indicating that mitochondrial dysfunction may drive senescence independent of ROS production; however, other models suggest that mitochondrial ROS may drive nuclear DNA damage or downstream signaling events that result in senescence and the SASP. It is therefore unclear if reducing mitochondrial ROS is effective in reducing the burden of senescent cells or the SASP during natural aging.

Here, we show that transgenic mCAT has no effect on senescent phenotypes in cultured human fibroblasts. Furthermore, gonadal adipose tissue from aged WT and mCAT mice shows increases in many markers of senescence both at 17 and after 25 months, but mCAT has no discernable effect on these markers. Together, these data support a model in which mitochondrial ROS are not universally required for senescence or the SASP during natural aging.

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Heat Stress Produces Lasting Cellular Resilience via Formation of Tetraspanin Webs

Research has shown that many forms of mild, transient stress result in lasting changes to cell behavior and modestly slowed aging in short-lived animal species. This is the case whether the stress involves heat, cold, or lack of nutrients. This is hormesis, that overall benefit can result from suffering mild stress and low levels of molecular damage. While researchers have identified improved activity of the cell maintenance processes of autophagy as an important mechanism in the beneficial response to mild stressors, it remains a work in progress to understand all of the details of the lasting hormetic response to transient stress.

In today's open access paper, researchers discover a novel way in which cells maintain a memory of their exposure to heat stress. The protein TSP-1 is a tetraspanin, and this type of protein is known to form arrangements known as webs in the cell membrane. When generated in response to heat stress these tetraspanin webs can be long-lasting, and thus provide the cell with a form of memory distinct from epigenetic marks or other changes affecting gene expression in the cell nucleus. In general, one might argue that complex structures that form in the cell membrane (such as lipid rafts) are understudied and poorly understood in comparison to the biochemistry of the cell nucleus.

Early-life stress triggers long-lasting organismal resilience and longevity via tetraspanin

Epidemiological and clinical studies in humans show that life stress of various forms can exert profound lasting impacts on mental and physical health outcomes and life spans. Milder physiological stresses, such as fasting with adequate nutrition or thermal stimuli via sauna exposure, are associated with long-lasting health benefits. Transient periods of stress can induce persistent changes in the endocrine response, epigenetic regulation of gene expression, and plasticity changes in various organs. However, the underlying molecular and cellular mechanisms by which transient early-life stress can produce memory-like physiological effects remain poorly understood.

The free-living nematode Caenorhabditis elegans has emerged as a tractable model system to study how early-life stress may affect adult phenotypes. Adults that have undergone the dauer stage preserve a memory of their early-life starvation experience, resulting in alterations in gene expression, extended life span, and decreased reproductive capacity. In addition, a 1-day shift from 20° to 25°C during early adulthood in C. elegans appears to improve stress resistance and extend life span through known stress-responding transcription factors: Forkhead box transcription factor (DAF-1), heat shock transcription factor (HSF-1), and hypoxia inducible transcription factor (HIF-1). It remains unclear how specific effectors of these transcription factors, or other epigenetic mechanisms independent of these factors, may elicit long-lasting impacts on adult stress resilience and longevity.

In this study, we use a robust thermal stress paradigm in C. elegans to uncover causal mechanisms by which transient stress may exert lasting impacts on organismal resilience and longevity. We show that transient heat exposure at 28°C during late larval development activates the gene tsp-1, which encodes a C. elegans homolog of the evolutionarily conserved tetraspanin protein family. Tetraspanin 1 (TSP-1) proteins form tetraspanin web-like structures and are essential for maintaining membrane permeability, barrier functions, and heat-induced organismal resilience and longevity. Initial induction of tsp-1 by heat requires the histone acetyltransferase CBP/p300 homolog (CPB-1); however, unexpectedly, this results in sustained up-regulation of TSP-1 protein without a corresponding increase in mRNA abundance.

Our data suggest that tsp-1 expression leads to TSP-1 protein multimerization and the formation of stable tetraspanin web structures, which persist even in the absence of initial stimuli and tsp-1 transcript up-regulation. This tetraspanin web-based stable protein structure formation represents an intriguing mechanism of cellular memory, distinct from previously known modes of epigenetic regulation primarily occurring in the nucleus, such as DNA and histone modifications.

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Arguing for Low Glutathione Levels to be Important in the Development of Parkinson's Disease

Glutathione is one of the more important cellular antioxidants. Delivery of glutathione via a range of mechanisms has been tested as a way to improve function in older individuals, with intriguing results in small clinical trials. The benefits include improved mitochondrial function and reduced inflammation. Delivery of antioxidants to mitochondria, where they can suppress the production of reactive oxygen species that takes place as a side-effect of the normal operation of these organelles, has been demonstrated to improve health and modestly slow aging in animal models. Unfortunately glutathione isn't orally bioavailable; one can't just take it as a supplement. Intravenous injection works, but the most interesting of the tested delivery methods are iontophoresis patches and daily supplementation with large amounts of the gluthathione precursors glycine and N-acetylcysteine.

In this context, one might take a look at today's open access paper. It is interesting to see the evidence presented for low glutathione levels to contribute to the development of Parkinson's disease. The most evident symptoms of the condition derive from cell death in the small but vital population of dopamine-generating neurons. These neurons are evidently more vulnerable to stresses, including oxidative stress deriving from mitochondrial dysfunction, than is the case for other cells in the brain. Glutathione is protective, and the less of it there is, the greater the risk of losing enough dopamine-generating neurons to tip over into the symptoms of Parkinson's disease.

Natural Variation in Age-Related Dopamine Neuron Degeneration is Glutathione-Dependent and Linked to Life Span

Aging is the biggest risk factor for Parkinson's disease (PD), suggesting that age-related changes in the brain promote dopamine neuron vulnerability. It is unclear, however, whether aging alone is sufficient to cause significant dopamine neuron loss and if so, how this intersects with PD-related neurodegeneration. Here, through examining a large collection of naturally varying Drosophila strains, we find a strong relationship between life span and age-related dopamine neuron loss. Strains with naturally short-lived animals exhibit a loss of dopamine neurons but not generalized neurodegeneration, while animals from long-lived strains retain dopamine neurons across age.

Metabolomic profiling reveals lower glutathione levels in short-lived strains which is associated with elevated levels of reactive oxygen species (ROS), sensitivity to oxidative stress and vulnerability to silencing the familial PD gene parkin. Strikingly, boosting neuronal glutathione levels via glutamate-cysteine ligase (Gcl) overexpression is sufficient to normalize ROS levels, extend life span, and block dopamine neurons loss in short-lived backgrounds, demonstrating that glutathione deficiencies are central to neurodegenerative phenotypes associated with short longevity.

These findings may be relevant to human PD pathogenesis, where glutathione depletion is reported to occur in idiopathic PD patient brain through unknown mechanisms. Building on this, we find reduced expression of the Gcl catalytic subunit in both Drosophila strains vulnerable to age-related dopamine neuron loss and in human brain from familial PD patients harboring the common LRRK2 G2019S mutation. Our study across Drosophila and human PD systems suggests that glutathione synthesis and levels play a conserved role in regulating age-related dopamine neuron health.

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Request for Startups in the Rejuvenation Biotechnology Space, 2024 Edition

Investors focused on funding biotechnology startups tend to exhibit herd behavior, much like investors everywhere these days. Funding is primarily deployed towards fads and popular trends, not necessarily towards what makes the most sense, even if sometimes the sensible manages to align with the popular. These days that means drug discovery platforms with a strong computational component and partial epigenetic reprogramming. But even in this environment, the path to true success is to work on important projects that few other people are touching. Be the champion for a potential solution to a tough, high-value, comparatively neglected problem.

Considering those tough, high-value problems, we can look at the world as it stands today and count how many people die from this age-related condition or that age-related condition. We could start at the top and work down: atherosclerosis, cancer, viral infection, dementia, kidney disease. All of these categories are vast, worldwide, with room for a sizable number of companies to all achieve significant success. For each of the categories of mortality mentioned above, there is room for many different therapies that address some part of the complex web of mechanisms of aging that lead to disease and death.

More First in Class Treatments for Atherosclerosis

The present state of therapy and development for the treatment of atherosclerosis is dismal. Industry and regulators are fixated on lowering LDL-cholesterol in the bloodstream, an approach that has demonstrably and comprehensively failed to reverse established atherosclerotic plaque, only slowing the progression of the condition modestly. The still-standard small molecule therapies, statins, have meaningful unpleasant, dose-limiting side-effects for a sizable fraction of patients. New development remains near entirely focused on novel ways of lowering LDL-cholesterol, none of which are shown to do any better than statins when it comes to the most important outcome, which is to say reversing the growth of atherosclerotic plaque. Outsider biotech startups like Cyclarity Therapeutics and Repair Biotechnologies cannot continue to be the only groups developing novel, different, ambitious therapies aimed at reversal of atherosclerosis. There is a vast gap in the market, an enormous unmet need in the 26% of humanity that is killed by stroke and heart attack, the direct consequences of unstable atherosclerotic plaques. This ongoing toll takes place in a world in which everyone who can use statins is using statins. We must do better.

More Attempts at a Universal Cancer Therapy

A good number of mechanisms involved in cancer are, if not completely universal to all cancer cells, at least common across a sizable fraction of all cancers. Far too little work is focused on influencing these mechanisms. Finding ways to interfere in alternative lengthening of telomeres (ALT), for example, continues to languish despite being an excellent target for small molecule development, given that ALT only operates in cancerous cells. As the rapid progress of Maia Biotechnology demonstrates, a broadly applicable cancer therapy (targeting telomere extension in their case) will quickly draw the attention of well-funded backers in an industry that has hobbled itself by focusing discovery on uncovering per-cancer and per-cancer-subtype mechanisms without broad application.

Far Better Antiviral Therapies

Present antiviral therapies are a mixed bag, all too few of which are truly effective. Herpesviruses and similar viral infections that persist over years and decades are implicated in the decline of the immune system and development of age-related diseases. The failing immune system also allows influenza and similar respiratory viruses to transiently infect and kill immense numbers of older people every year. There are too few approaches under development, such as the successor to the DRACO methology at Kimer Med, aimed at the production of improved antiviral therapies that are not just more effective for some viral infections, but can also target many different viruses with minimal alteration to the therapy itself.

Means to More Selectively Suppress Excessive Inflammation

The chronic inflammation of aging is highly disruptive to tissue function and drives the progression of many of the common fatal age-related conditions. This maladaptive, unresolved inflammatory response derives from a wide range of processes, everything from the persistent viral infections mentioned above through to a growing burden of senescent cells, bad behavior on the part of visceral fat cells, innate immune reactions to mitochondrial stress and mislocated mitochondrial DNA, and much more besides. So far, research into the biochemistry of inflammatory signaling suggests that both useful, short-term inflammatory reactions and harmful, excessive, unresolved inflammatory reactions run through the same signaling pathways. This is not a certain conclusion, however. If it is the case, then the only way to dampen the chronic inflammation of aging without also suppressing necessary immune function is to fix every dysfunction of aging. Are there short-cuts, however, ways to interfere in only the unwanted inflammatory signaling? Perhaps.

Infrastructure for Faster, Cheaper, Responsible Clinical Trials

There is a huge gap in the options available for clinical development of therapies. Moving forward within the established FDA or EMA system, requiring expensive GMP manufacturing processes and trial infrastructure is excessively costly and far too cautious for near all therapies entering this process. Options such as holding formal clinical trials outside the US, with Australia being a popular location, do not reduce the cost by anywhere near enough. Alternatively one can deploy therapies in clinics outside the US and offer services via medical tourism, suffering all of the consequences thereof, such as lack of public trust and low numbers of patients.

Where is the middle ground between these two points? Sadly, there is no established middle ground whereby responsible clinical trials can be conducted within a system with a good reputation, outside the FDA and EMA systems, making full use of the low cost options of sites such as Próspera in Honduras. Not all medical therapies need GMP manufacture for reasonable degrees of safety. Not all medical therapies need heavy-duty trial infrastructure to provide sufficient proof of safety and efficacy to convince physicians to use them. If we want faster progress, then the costs of medical development must be greatly reduced. Groups associated with the Próspera project are among the few presently attempting to build this middle ground - but there is a great deal of room for competition in the production of a low-cost, responsible, trusted alternative to the FDA and EMA.

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Restriction of RNA Polymerase I Activity Extends Life in Nematode Worms

RNA Polymerase I (Pol I) is prominent in the regulatory systems managing the nutrient-driven tradeoff between growth and longevity. It is responsible for producing a sizable fraction of RNA, reading from gene sequences and assembling corresponding RNA molecules. As such, it is responsible for initiating some of the most energetically expensive processes in the cell, including translation of messenger RNA into proteins. Suppression of the production of proteins is a consequence of low calorie intake, an intervention known to slow aging, and researchers have shown that interfering in RNA synthesis can also extend life in short-lived species. Here, researchers dig further into the connection between Pol I activity and aging, showing that reduced Pol I activity extends life in nematode worms.

The insulin/insulin-like growth factor signaling (IIS) and the mechanistic target of rapamycin (mTOR) promote anabolic reactions upon nutrient availability, whereas in a fasted state the adenosine monophosphate-activated protein kinase (AMPK) and the sirtuin family of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases trigger catabolic processes. Shifting the balance from IIS and mTOR signaling towards AMPK and sirtuin activity by diverse interventions promotes longevity in short-lived species.

The IIS, mTOR, AMPK, and sirtuin pathways impinge on Pol I-mediated transcription of ribosomal RNA (rRNA) genes (rDNA) into pre-rRNA, a precursor transcript comprising the three largest rRNAs. Notably, Pol I activity accounts for the major part of cells' transcription and, together with pre-rRNA processing and synthesis of ribosomal proteins, consumes a large portion of the cellular biosynthetic and energetic capacity. Moreover, ribosome biogenesis is required for mRNA translation, placing pre-rRNA synthesis at the origin of the most energy-demanding cellular activities.

Two recent studies reported that perturbation of rRNA synthesis entails pro-longevity effects in C. elegans and D. melanogaster, either by inducing structural changes in the nucleolus, the organelle implicated in ribosome biogenesis, or by limiting protein synthesis, respectively. However, the interplay between metabolic costs of Pol I activity and aging has not been explored in these studies.

Here we use multi-omics and functional tests to show that curtailment of Pol I activity remodels the lipidome and preserves mitochondrial function to promote longevity in C. elegans. Reduced pre-rRNA synthesis improves energy homeostasis and metabolic plasticity also in human primary cells. Conversely, the enhancement of pre-rRNA synthesis boosts growth and neuromuscular performance of young nematodes at the cost of accelerated metabolic decline, mitochondrial stress, and premature aging. Moreover, restriction of Pol I activity extends lifespan more potently than direct repression of protein synthesis, and confers geroprotection even when initiated late in life, showcasing this intervention as an effective longevity and metabolic health treatment not limited by aging.

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A Genome-Wide Genetic Association Study of Sleep Duration and Longevity

Researchers here use Mendelian randomization to attempt to better understand the relationship between sleep duration and later life mortality. As is well established, a short sleep duration correlates with raised mortality. The point of performing this sort of study of genetic variants and their relationship with specific outcomes is to try to tease out evidence for causation. Epidemiological studies can only provide correlations between sleep duration and increased mortality risk, but genetic studies can provide at least some support for the idea that short sleep duration actually causes a meaningful degree of that increased mortality risk, and isn't just a side-effect of some sort.

Poor sleep health is associated with a wide array of increased risk for cardiovascular, metabolic, and mental health problems as well as all-cause mortality in observational studies, suggesting potential links between sleep health and lifespan. However, it has yet to be determined whether sleep health is genetically or/and causally associated with lifespan.

In this study, we firstly studied the genome-wide genetic association between four sleep behaviors (short sleep duration, long sleep duration, insomnia, and sleep chronotype) and lifespan using GWAS summary statistics, and both sleep duration time and insomnia were negatively correlated with lifespan. Then, two-sample Mendelian randomization (MR) and multivariable MR analyses were applied to explore the causal effects between sleep behaviors and lifespan.

We found that genetically predicted short sleep duration was causally and negatively associated with lifespan in univariable and multivariable MR analyses, and this effect was partially mediated by coronary artery disease (CAD), type 2 diabetes (T2D), and depression. In contrast, we found that insomnia had no causal effects on lifespan. Our results further confirmed the negative effects of short sleep duration on lifespan and suggested that extension of sleep may benefit the physical health of individuals with sleep loss. Further attention should be given to such public health issues.

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Searching for a Causal Link Between Gut Microbiome Populations and Pace of Aging

Mendelian randomization is a strategy for using genetic variants associated with specific phenotypes and outcomes to produce data supportive of a causal relationship between phenotype to outcome. Here, researchers aim to find evidence that larger populations of specific microbial species in the gut microbiome can speed up or slow down the process of degenerative aging, as assessed by aging clocks derived from simple health measures. The relative sizes of the microbial populations making up the gut microbiome shift with age, and research to date has demonstrated that the overall effects of these changes are negative: more pro-inflammatory microbes, fewer microbes producing beneficial metabolites. There are proven ways to produce lasting rejuvenation of the aged gut microbe, resetting the balance of populations, such as via fecal microbiota transplant from a young individual, but these interventions are not yet widely used.

Increasing evidence suggests that gut microbiota play an important role in the aging process. The gut microbiome, the collection of microorganisms inhabiting the human gastrointestinal tract, emerged as a key player in regulating host physiology and health. The gut microbiota begin to colonize the body from birth and develop together with the individual, playing a role in different stages of an individual's life. Accumulating evidence indicates that alterations in the gut microbiota composition and function, collectively referred to as dysbiosis, are associated with age-related diseases and may contribute to the aging process.

Observational studies cannot infer causal relationships between exposure and outcomes, and randomized controlled trial (RCT) studies often require a lot of research funding and costs and are constrained by experimental design limitations. Mendelian randomization (MR) uses genetic variation as an instrumental variable to infer causal relationships between exposures and outcomes from non-experimental data. Using MR has identified causal relationships between gut microbiota and aging-related diseases such as cardiovascular diseases and neurodegenerative diseases. MR studies also found causal relationships between gut microbiota and longevity. However, no MR studies have yet demonstrated a causal relationship between gut microbiota and biological aging.

In this study, two-sample MR was used to analyze the causal relationship between gut microbiota and biological aging in order to explore whether specific gut microbiota accelerate or decelerate the biological aging process and to provide new insights into promoting healthy aging through the modulation of gut microbiota. Streptococcus (β = 0.16) was causally associated with Bioage acceleration. Eubacterium (β = 0.20), Sellimonas (β = 0.06), and Lachnospira (β = -0.18) were suggestive of causal associations with Bioage acceleration, with the latter being protective. Actinomyces (β = 0.26), Butyricimonas (β = 0.21), and Lachnospiraceae (β = 0.24,) were suggestive of causal associations with Phenoage acceleration.

In conclusion, this Mendelian randomization study found that Streptococcus was causally associated with Bioage acceleration. Further randomized controlled trials are needed to investigate its role in the aging process.

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Considering the Mechanisms of Vascular Calcification

Harmful calcification of structures in the cardiovascular system proceeds alongside the development of the fatty lesions of atherosclerosis. Both disease processes are accelerated by chronic inflammation, but derive from very different, distinct underlying mechanisms. There is presently little that can be done to reverse calcification effectively; EDTA chelation therapy is the best option on the table at present, but isn't well regarded in the medical community. Other treatments are more focused on slowing the progression of calcification, and can achieve that goal to some degree.

The primary cause of worldwide mortality and morbidity stems from complications in the cardiovascular system resulting from accelerated atherosclerosis and arterial stiffening. Frequently, both pathologies are associated with the pathological calcification of cardiovascular structures, present in areas such as cardiac valves or blood vessels (vascular calcification). The accumulation of hydroxyapatite, the predominant form of calcium phosphate crystals, is a distinctive feature of vascular calcification. This phenomenon is commonly observed as a result of aging and is also linked to various diseases such as diabetes, chronic kidney disease, and several genetic disorders.

A substantial body of evidence indicates that vascular calcification involves two primary processes: a passive process and an active process. The physicochemical process of hydroxyapatite formation and deposition (a passive process) is influenced significantly by hyperphosphatemia. However, the active synthesis of calcification inhibitors, including proteins and low-molecular-weight inhibitors such as pyrophosphate, is crucial. Excessive calcification occurs when there is a loss of function in enzymes and transporters responsible for extracellular pyrophosphate metabolism.

In clinical practice, it is crucial to assess phosphate and pyrophosphate homeostasis by evaluating both plasma phosphate and pyrophosphate levels. When elevated phosphate levels are detected in the blood, the initial therapeutic strategies to prevent vascular calcification should include the administration of phosphate binders to reduce circulating phosphate levels and address any dysregulated phosphate homeostasis if present. Furthermore, in cases of low pyrophosphate levels, therapeutic strategies should involve the administration of exogenous pyrophosphate and interventions to enhance the availability of endogenous pyrophosphate.

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Blood Tests for Alzheimer's Disease Continue to Look Promising

In recent years, data has shown correlations between specific blood biomarkers and Alzheimer's disease pathology in the brain, such as the burden of misfolded, aggregated amyloid-β. This has led to the development of a variety of blood tests for Alzheimer's disease, intended to replace the presently onerous testing that requires either expensive imaging or invasive analysis of cerebrospinal fluid. Alzheimer's disease develops slowly over time, a long period of raised amyloid-β levels in the brain setting the stage for later dysfunction. Early testing for the risk of later Alzheimer's disease enabled attempts to slow or evade the condition, such as via lifestyle changes, use of antiviral therapies, or at worst undergoing immunotherapies to reduce the burden of amyloid-β in the brain.

Accurate and expeditious detection of Alzheimer's disease (AD) pathology continues to be a major hurdle in advancing AD-modifying clinical research. A robust screening process that can identify patients with a high probability to randomize into AD therapeutic research trials would greatly enhance the ability to conduct and reduce the time needed to complete clinical trials. AD is characterized by the accumulation of two protein aggregates in the brain: extracellular deposits of amyloid beta (Aβ)-containing plaques and intraneuronal aggregates of misfolded tau protein. Numerous AD clinical trials, particularly those targeting either Aβ or amyloid plaques have used amyloid PET scans and/or cerebrospinal fluid (CSF) measures as an inclusion criterion for enrollment. While amyloid PET tracers have been shown to be very accurate in detecting brain amyloid deposits, these scans are costly and impose a significant patient burden.

Blood-based measures that are associated with the presence of brain amyloid plaques have recently been developed. Additionally, there is substantial interest in blood-based biomarkers reflecting two other critical aspects of AD pathology: tau tangles and neurodegeneration. Several clinical studies have been conducted evaluating the ability of various blood-based biomarkers to identify AD. These studies have identified Aβ40, Aβ42, the Aβ42/Aβ40 ratio (Aβ42/Aβ40), tau, and several species of phosphorylated tau (p-tau) as good candidates.

The primary objective of the Bio-Hermes Study was to evaluate the ability of several promising blood-based and digital biomarkers to reflect the presence of brain amyloid in participants enrolled at clinical trial sites using recruitment procedures similar to those used in AD therapeutic drug studies. Participants in the Bio-Hermes Study had clinical characteristics similar to those enrolled in clinical trials of disease-modifying treatments and, because multiple biomarkers were obtained, the predictive value of biomarkers alone or in combination can be evaluated. Results indicate that Aβ42/Aβ40 ratio, p-tau181, and p-tau217 are good predictors of brain amyloid positivity in this clinical trial-ready population.

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Supporting Evidence for Inactivity and Chronic Inflammation to be Important in Muscle Aging

It is well known that muscle function can be sustained into late life to a greater degree than most people manage. Much of what is presently considered by most people to be normal loss of strength and muscle mass with aging is the result of a combination of a lack of exercise combined with lifestyle choices, such as becoming overweight, that generate chronic inflammation. Researchers here illustrate the point in a study of gene expression changes that take place in muscle tissue with age and other factors. The researchers compared age versus exercise and inflammatory status. At least by looking at the number of changes, chronological age has less of an effect on gene expression in muscle tissue than is the case for exercise and inflammation.

Evaluation of the influence of primary and secondary aging on the manifestation of molecular and cellular hallmarks of aging is a challenging and currently unresolved issue. Our study represents the first demonstration of the distinct role of primary aging and chronic inflammation/physical inactivity - the most important drivers of secondary aging, in the regulation of transcriptomic and proteomic profiles in human skeletal muscle. To achieve this purpose, young healthy people (n = 15), young (n = 8) and older (n = 37) patients with knee/hip osteoarthritis, a model to study the effect of long-term inactivity and chronic inflammation on the vastus lateralis muscle, were included in the study.

It was revealed that widespread and substantial age-related changes in gene expression in older patients relative to young healthy people (~4000 genes regulating mitochondrial function, proteostasis, cell membrane, secretory and immune response) were related to the long-term physical inactivity and chronic inflammation rather than primary aging. Primary aging contributed mainly to the regulation of genes (~200) encoding nuclear proteins (regulators of DNA repair, RNA processing, and transcription), mitochondrial proteins (genes encoding respiratory enzymes, mitochondrial complex assembly factors, regulators of cristae formation and mitochondrial reactive oxygen species production), as well as regulators of proteostasis. It was found that proteins associated with aging were regulated mainly at the post-transcriptional level.

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Investigating the Role of S6K in the Slowed Aging Produced by Rapamycin

Decreased S6K expression is one of the downstream consequences of treatment with the mTOR inhibitor rapamycin, and is essential for mTOR inhibition to extend life in mice and other laboratory species. It is thought that the slowing of aging resulting from mTOR inhibition largely works via improved operation of the complex cell maintenance processes of autophagy, wherein damaged proteins are flagged, wrapped in membranes, and conveyed to a lysosome for recycling. Researchers here investigate the role of S6K, and note that it appears to reduce the excessive inflammatory signaling characteristic of old age in addition to improving lysosomal function, and thus autophagy.

Although S6K is a key downstream effector of mTOR signaling and has been implicated in determination of lifespan in invertebrates and mammals, the molecular and cellular mechanisms are still elusive. Here we show that, in Drosophila, lowered activity of S6K in the fat body is essential for mTOR-dependent longevity, and that it regulates endolysosomal morphology, inflammaging, and immunosenescence in the aging fat body.

Modifying endosome formation, but not autophagy, affected inflammaging by degrading rPGRP-LC, suggesting a causal link between endolysosome and inflammaging. We identified Syx13 as a molecular link that regulates endosome formation, inflammaging, and lifespan downstream of TORC1-S6K signaling. We uncovered a considerable sexual dimorphism in fat body inflammaging, potentially explaining the different lifespan impacts of S6K observed in males and females. Furthermore, repression of the NF-κB-like IMD pathway in the fly fat body enhanced clearance of bacteria and extended lifespan.

Importantly, long-term treatment with rapamycin increased Stx12 levels in mouse liver, and alleviation of immune processes was a common denominator of TORC1-S6K inhibition in RNA and proteomics profiles from the liver of old rapamycin-treated and S6K1 knockout mice. Furthermore, Rapa lowered age-associated activation of noncanonical NF-κB pathway in mouse liver, indicating that the effects of TORC1-S6K-Stx12 on immunoaging may be evolutionarily conserved from flies to mice. In summary, our findings highlight an important role for the TORC1-S6K-Syx13 signaling axis in inflammaging, immunosenescence and longevity.

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Continuing the Debate Over Why Time Spent Sitting Correlates with Mortality

You might recall a number of epidemiological studies from the past fifteen years that examined correlations between time spent sitting and late life mortality. Some demonstrated that regardless of degree of physical activity sitting time still correlated with mortality - not the most intuitive of outcomes. As is the case for all such epidemiological questions of lifestyle and mortality, the general thrust of the data was disputed by a few large opposing studies. One in particular argued that the focus on sitting was misplaced, early studies misinterpreted their data, and that the focus should be on immobility. In support of that idea, accelerometer studies have consistently shown that low levels of activity, such as gentle walking, gardening, moving around in the house, are significantly better for long-term health than being entirely sedentary. Still, the debate on sitting continues, as shown here.

Sedentary behavior is a recognized mortality risk factor. The novel and validated convolutional neural network hip accelerometer posture algorithm highly accurately classifies sitting and postural changes compared with accelerometer count cut points. We examined the prospective associations of convolutional neural network hip accelerometer posture-classified total sitting time and mean sitting bout duration with all-cause and cardiovascular disease (CVD) death.

Women (n=5,856; 79±7 years old) in the Women's Health Initiative Objective Physical Activity and Cardiovascular Health (OPACH) Study wore the ActiGraph GT3X+ for ~7 days from May 2012 to April 2014 and were followed through February 19, 2022 for all-cause and CVD death. The convolutional neural network hip accelerometer posture algorithm classified total sitting time and mean sitting bout duration from GT3X+ output. Over a median follow-up of 8.4 years there were 1,733 deaths, 632 of which were from CVD. Adjusted Cox regression hazard ratios (HRs) comparing women in the highest total sitting time quartile (more than 696 minutes per day) to those in the lowest (less than 556 minutes per day) were 1.57 for all-cause death and 1.78 for CVD death. HRs comparing women in the longest mean sitting bout duration quartile (more than 15 minutes) to the shortest (less than 9.3 minutes) were 1.43 for all-cause death and 1.52 for CVD death. Apparent nonlinear associations for total sitting time suggested higher all-cause death and CVD death risk after ~660 to 700 minutes per day.

Higher total sitting time and longer mean sitting bout duration are associated with higher all-cause and CVD mortality risk among older women. These data support interventions aimed at reducing both total sitting time and interrupting prolonged sitting.

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A Way in Which Mitochondrial DNA Becomes Misplaced, Provoking Inflammation

Cells respond to the presence of DNA in the cytoplasm with inflammatory signaling, an evolved innate immune response that serves to protect against viral and bacterial infection. This becomes a problem when mitochondria become dysfunctional, as mitochondria contain their own small genome, the mitochondrial DNA. In the context of age-related mitochondrial dysfunction, and a number of other circumstances, fragments of mitochondrial DNA can find their way into the cell cytoplasm. The result is a link between mitochondrial dysfunction and the chronic inflammation of aging, though it remains unclear as to how much of this characteristic unresolved inflammatory signaling is the result of mislocated DNA versus, say, the presence of senescent cells, or other contributions. Is there something that can be done to block this unwanted inflammatory signaling, short of repairing or replacing dysfunctional mitochondria throughout the body? Perhaps, perhaps not, but further research is the only way to find out.

Mitochondrial DNA (mtDNA) encodes essential subunits of the oxidative phosphorylation system, but is also a major damage-associated molecular pattern (DAMP) that engages innate immune sensors when released into the cytoplasm, outside of cells or into circulation. As a DAMP, mtDNA not only contributes to anti-viral resistance, but also causes pathogenic inflammation in many disease contexts. Cells experiencing mtDNA stress caused by depletion of the mtDNA-packaging protein, mitochondrial transcription factor A (TFAM) or during herpes simplex virus-1 infection exhibit elongated mitochondria, enlargement of nucleoids (mtDNA-protein complexes) and activation of cGAS-STING innate immune signalling via mtDNA released into the cytoplasm. However, the relationship among aberrant mitochondria and nucleoid dynamics, mtDNA release, and cGAS-STING activation remains unclear.

Here we show that, under a variety of mtDNA replication stress conditions and during herpes simplex virus-1 infection, enlarged nucleoids that remain bound to TFAM exit mitochondria. Enlarged nucleoids arise from mtDNA experiencing replication stress, which causes nucleoid clustering via a block in mitochondrial fission at a stage when endoplasmic reticulum actin polymerization would normally commence, defining a fission checkpoint that ensures mtDNA has completed replication and is competent for segregation into daughter mitochondria. Chronic engagement of this checkpoint results in enlarged nucleoids trafficking into early and then late endosomes for disposal. Endosomal rupture during transit through this endosomal pathway ultimately causes mtDNA-mediated cGAS-STING activation. Thus, we propose that replication-incompetent nucleoids are selectively eliminated by an adaptive mitochondria-endosomal quality control pathway that is prone to innate immune system activation, which might represent a therapeutic target to prevent mtDNA-mediated inflammation during viral infection and other pathogenic states.

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An Example of the Decomposition of Signatures of Aging into Multiple Distinct Trends

Gero is one of a number of longevity industry biotech companies that put a strong focus on computational analysis of data to steer small molecule drug development and repurposing efforts. One of the interesting themes in their papers and presentations is the decomposition of signatures of aging into different distinct components, both in mice and in humans. When one can identify different overlapping trends in age-related changes in omics data, there is something to be said in that about the way in which aging progresses. The usual challenges apply, however, in that it is difficult to take this sort of analysis and link it back to fundamental mechanisms of aging. The research community as a whole struggles to identify concrete links between specific forms of molecular damage and consequential dysfunction on the one hand versus specific changes in biomarkers on the other. There is an enormous body of data, and data has become cheap to manufacture, but obtaining a deeper understanding of the meaning of that data remains a slow and expensive process.

Aging across most species, including mice and humans, is characterized by an exponential acceleration of mortality rates. In search for the molecular basis of this phenomenon, we analyzed DNA methylation (DNAm) changes in aging mice. Utilizing principal component analysis (PCA) on DNAm profiles, we identified a primary aging signature with an exponential age dependency, closely reflecting the Gompertz law's description of mortality acceleration.

This signature is the manifestation of the dynamic instability in the organism's state that drives the aging process in mice. It aligns closely with regression-based aging clocks and responds to interventions such as caloric restriction and parabiosis. Additionally, we identified a linear DNAm signature, indicative of a global demethylation level. Through single-cell DNAm (scDNAm) data from aging animals, we demonstrate that this signature captures the exponential expansion of the state space volume spanned by individual cells within an aging organism, and thus quantifying linearly increasing configuration entropy, likely an irreversible process. Consistent with this interpretation, we found that neither caloric restriction (CR) nor parabiosis significantly impacts the entropic feature, reinforcing its link to irreversible damage.

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