Fight Aging! Newsletter, May 15th 2023

It has been proposed that epigenetic changes are causative in ageing, and a recent study has suggested that DNA damage response-induced loss of epigenetic information drives ageing. More broadly, the information theory of ageing has suggested that loss of epigenetic information with age is a major driver of the ageing process. It has also been suggested that pre-programmed shifts in epigenetic information states with age are a major determinant of ageing phenotypes. As such, understanding the basis of epigenetic clocks, and how epigenetic changes could impact ageing is a major and important open question. Moreover, despite efforts to understand the informatic character of ageing, there has been comparatively little research on what makes mammalian ageing inevitable.

In this work, we develop a conceptual model to explain the ageing process based on first principles. We demonstrate that the epigenetic system has unique inherent informatic properties that progressively acquire informatic corruption, meaning that with age epigenetic information fidelity cannot be maintained. In this work we set out to break down the nature of epigenetic damage and characterise biological ageing as a failure of repair fidelity.

To do this, we began by showing that chronological age correlates to the progressive deviation within certain classes of CpG loci. It seems that there are three variables that control the correlation to age: those values representing fluke correlation to cellular regulation, those representing genes that are being regulated increasingly as age increases (senescence, DNA repair, stress response, etc) and those peaks describing epigenetic systems becoming deregulated with age. We suggest that epigenetic clocks are measuring both of the latter classes of CpG and that the answer to the question 'Are epigenetic clocks measuring cause or consequence' is 'both', depending on the CpGs used.

Genes that change in response to age represent the effect of age and the epigenetic stochastic noise represents biological age itself. We propose that this epigenetic damage would result in a feedback cycle, in which deregulation would lead to further deregulation through the disruption of maintenance and repair of the epigenetic regions, and to the phenotype of age through the general deregulation of cellular systems. This would fit the profile of ageing as a robust, gradual process, with slow, reliable progress made as deregulation accumulates, accelerating toward network failure as the feedback cycle picks up pace.

We can see in the gene ontology results that in all organisms and tissues, those genes regulated by the loci in which deregulation correlates to age are genes governing promotors and enhancers. We suggest that this is because promotors and enhancers have a unique feature that precludes polarising their regional control for regulation: they need to regularly reconfigure the local methylation state consequent to the current state of transcription.

We suggest this makes them tautologically defined, in that the definition of the epigenetic signal of a promotor/enhancer modulator relies in part on its own current state (such that any damage results in damage to any rule from which the signal could be corrected), and thus representing a class of loci in which epigenetic regional control cannot be correctly defined once epigenetic damage has occurred. We suggest damage accrues in these regions and the global deregulation of transcription that occurs consequent to this gives rise to the general phenotype of age.

In this study, we examined the average telomere length and telomerase activity, as well as the formation of telomere associated foci (TAFs) and the mRNA expression levels of the shelterin components in cultured primary cells of Spalax, a long-lived, hypoxia-tolerant, and cancer-resistant blind mole-rat species.

We showed that with cell passages, Spalax fibroblasts demonstrated significant shortening in telomere length, similar to rat cells, and in line with the processes observed earlier in tissues. We also demonstrated that the average telomere length in Spalax fibroblasts was significantly higher than the average length in rats, similar to previously reported results in Spalax muscles. Long telomeres are controversially described in the literature by their association with cancer risk, aging, or longevity. Extremely long telomeres in mice were reported to produce beneficial metabolic effects, low cancer risks, and longevity. Whether the long, seemingly guarded telomeres are one of the driving forces in Spalax longevity and healthy aging remains unclear.

It may be speculated that longer telomeres are attributed to telomerase overexpression, which presumably prolongs cell survival; however, we found that Spalax fibroblast telomerase activity was, in fact, lower than that of its counterpart in rats, which further supports our hypothesis that integrity maintenance of the telomeres (such as via shelterin activity), rather than telomere elongation, is characteristic of Spalax cells as a strategy that contributes to its long lifespan and supports its unique mode of cellular senescence.

It was suggested that long-lived animals have adopted a mechanism whereby the pace of telomere attrition and the activity of the telomerase is the same as that in other, short-lived animals. However, since initially, Spalax exhibits longer and potentially safeguarded telomeres, it seems tempting to speculate that the time it takes to reach critical length/damage that ignites the senescence machinery is longer and therefore, may contribute to their profoundly unique mode of replicative senescence lacking the canonical inflammatory response known to accompany the senescent phenotype in all studied species.

In summary, our results support that Spalax have evolved strategies for genome protection that apparently include telomere maintenance machinery, together contributing to its longevity and healthy aging. These strategies include a unique mode of senescence not induced by persistent DNA damage response (DDR) or telomere attrition, but which rather seems to be an independent cell program driven by other types of 'clocks'. The precise mechanisms of telomere maintenance and the apparently 'non-canonical senescence clock' require further investigation in Spalax and other long-lived species as possible requisites for long lifespan and healthy aging.

Changes in organelle morphology or function are a characteristic of aging, among which mitochondrial degeneration is most prominent. Mitochondria exhibit structural changes such as significant increases in volume and size due to the buildup of defective mitochondria. Defective mitochondria generate reactive oxygen species (ROS) as a byproduct of electron leakage from the electron transport chain (ETC). Not only are defective mitochondria ROS generators, but they are also targets of mitochondrial oxidative stress, which then boosts mitochondrial ROS production.

Mitochondrial ROS generated by defective mitochondria deteriorate the morphology and function of organelles, consequently leading to aging and age-related diseases. Therefore, strategies to reduce mitochondrial oxidative stress may be beneficial as therapeutic approaches to aging and age-related diseases. The finding that treatment of senescent cells with ROS scavengers restored the senescent phenotype supports the usefulness of this strategy. Mitochondrial oxidative stress is a major cause of senescence and the consequent development of age-related diseases, so a deeper comprehension of the mechanisms that target and control mitochondrial oxidative stress is needed.

In this review, we investigated and discussed mitochondrial alterations and the consequent increase in mitochondrial oxidative stress. In addition, by examining the process through which mitochondrial oxidative stress progresses aging and aging-related diseases, we found that mitochondrial oxidative stress acts as a vicious feedback loop for aging. Here, we suggested mitochondrial oxidative stress as a potential target for aging. Therapeutic approaches to reduce mitochondrial oxidative stress have proven to be an important factor in treating aging and age-related diseases. However, clinical trials using non-mitochondria-targeted antioxidants have shown that non-mitochondria-targeted antioxidant therapies are not effective in the treatment of aging and age-related diseases. To complement these clinical findings, mitochondria-targeting antioxidants have recently been applied to various animal models, and there is growing evidence that mitochondria-targeting antioxidants have beneficial effects on aging and age-related diseases.

A new Alzheimer's drug slowed cognitive decline by 35%, according to late-stage trial results, raising the prospect of a second effective treatment for the disease. Donanemab met all goals of the trial and slowed progression of the condition by 35% to 36% compared with a placebo in 1,182 people with early-stage Alzheimer's, the drugmaker Lilly said. It comes after trial results published last year showed that lecanemab, made by Eisai and Biogen, reduced the rate of cognitive decline by 27% in patients with early Alzheimer's.

In patients on donanemab, 47% showed no signs of the disease progressing after a year, according to a statement issued by Lilly. That compared to 29% on a placebo. The drug resulted in 40% less decline in the ability to perform activities of daily living, the company said. Patients on donanemab also experienced a 39% lower risk of progressing to the next stage of disease compared to those on a placebo.

However, the company also reported side-effects. Brain swelling occurred in 24% of those on donanemab, with 6.1% experiencing symptoms, Lilly said. Brain bleeding occurred in 31.4% of the donanemab group and 13.6% of the placebo group. Lilly also said the incidence of serious brain swelling in the donanemab study was 1.6%, including two deaths attributed to the condition and a third death after an incident of serious brain swelling.

Post-translational modifications (PTMs) such as phosphorylation, acetylation, and ubiquitination play critical roles in regulating signalling pathways that control muscle protein synthesis and degradation during muscle growth. However, during muscle aging, PTMs such as oxidation and glycation can lead to the accumulation of damaged proteins and impair muscle function. Specifically, oxidative stress can increase protein carbonylation and reduce the activity of key muscle proteins. The role of PTMs in sarcopenia is complex. Phosphorylation, acetylation and methylation can impact the activity of crucial proteins involved in muscle protein synthesis and degradation, whereas glycation and advanced glycation endproduct (AGE) formation can contribute to the accumulation of damaged proteins and affect muscle function.

Although this review provides an overview of the role of several PTMs in muscle homeostasis, it is important to note that there may be other types of modifications that also play a significant role in regulating muscle function, such as cysteine oxidation, ADP-ribosylation, and neddylation. High-throughput profiling of protein modifications associated with muscle mass, strength and functions helps us to understand the pathogenesis of sarcopenia and explore new diagnostic and therapeutic strategies, for example, the use of serological peptide biomarkers derived from PTM of proteins in tissues of interest for diagnosing skeletal muscle injury.

In addition, crosstalk between PTMs in physio-pathological processes of muscle, such as muscle aging and sarcopenia, remains to be investigated. The order and timing of protein modifications may be important for specific cellular processes, such as signal transduction. In these cases, sequential modifications may create a molecular 'switch' that controls the downstream signalling pathway or signal output. For instance, ubiquitination followed by phosphorylation can target a protein for degradation, whereas phosphorylation followed by acetylation can alter protein-protein interactions.Therefore, elucidating PTM crosstalk based on large-scale clinical samples is important for precision medicine in muscle diseases.

Master athlete is a term applied to individuals typically aged 35 years and older, who exercise and compete on a regular basis in organized sports competitions with similar-aged individuals. Master athletes have been reported to be significantly healthier than the general population in a number of health outcomes, including numerous chronic diseases such as asthma, coronary heart disease, stroke, cancer (all types combined), depression, diabetes (type 1 diabetes mellitus, type 2 diabetes mellitus), hypercholesterolemia, hypothyroidism, osteoporosis, Parkinson's' disease, and peripheral arterial disease.

We assessed resting blood pressure (BP) in male and female World Masters Games (WMG) athletes. This was a cross-sectional, observational study which utilized an online survey to assess the blood pressure (BP) and other physiological parameters. A total of 2,793 participants were involved in this study. Significant differences were identified when comparing WMG athletes' resting BP results to the general Australian population with WMG athletes having a lower systolic BP and diastolic BP. Only 8.1% of the WMG athletes were found to be hypertensive compared to 17.2% in the general Australian population.

Older adults suffer more frequent and worse outcomes from sepsis, a critical illness secondary to infection. The reasons underlying this unique susceptibility are incompletely understood. Prior work in this area has focused on how the immune response changes with age. The current study, however, focuses instead on alterations in the community of bacteria that humans live with within their gut (i.e., the gut microbiome). The central concept of this paper is that the bacteria in our gut evolve along with the host and "age," making them more efficient at causing sepsis.

Prior research has focused on host factors as mediators of exaggerated sepsis-associated morbidity and mortality in older adults. This focus on the host, however, has failed to identify therapies that improve sepsis outcomes in the elderly. We hypothesized that the increased susceptibility of the aging population to sepsis is not only a function of the host but also reflects longevity-associated changes in the virulence of gut pathobionts.

We utilized two complementary models of gut microbiota-induced experimental sepsis to establish the aged gut microbiome as a key pathophysiologic driver of heightened disease severity. Further murine and human investigations into these polymicrobial bacterial communities demonstrated that age was associated with only subtle shifts in ecological composition but also an overabundance of genomic virulence factors that have functional consequence on host immune evasion. Escape of these age-conditioned pathogens from the intestinal lumen therefore leads to exaggerated sepsis severity.

We previously demonstrated elevated levels of miR-141-3p with age in human and murine bone marrow environments. We have also reported that miR-141-3p inhibits the osteogenic differentiation of bone marrow stromal cells. Several other groups have shown elevated levels of miR-141-3p in age-related diseases, such as neurodegenerative disorders, and cardiovascular diseases. The current study was designed to answer the critical question whether by inhibiting miR-141-3p during aging can we improve overall health, specifically systemic and musculoskeletal health. For this study, we treated mice at 15 months of age subcutaneously twice a week for three months.

Overall health depends on oxidative and inflammatory stress levels in tissue and organs. With advanced age, pro-inflammatory cytokines tend to be higher. In our study, we found that serum pro-inflammatory cytokine levels (TNF-α, IL-1β, IFN-γ) declined in the Anti-miR-141-3p treatment. Moreover, we found decreased M1 and increased M2 macrophage in splenocytes in the treated group. This suggested that Anti-miR-141-3p treatment helps in maintaining better immune health.

Maintaining musculoskeletal health is an important contributing factor to healthy aging and longevity. We, therefore, analyzed the effects of Anti-miR-141-3p on muscle and bone microstructure. We observed muscle fiber size was increased in the mice treated with Anti-miR-141-3p compared to the vehicle-treated group. As expected, we also observed better bone microstructure in Anti-miR-141-3p treated animals. Ours is the first study to demonstrate the treatment with Anti-miR-141-3p decreases systemic inflammation and improves musculoskeletal health in aged mice.

We hypothesized that miR-141-3p induces a determinate effect on aging cells through multiple signaling pathways, specifically by promoting a pro-inflammatory environment and inducing premature senescence. Our data demonstrated that treatment of cells in vitro with miR-141-3p elevated the expression of pro-inflammatory cytokines (TNF-α, IL-1β) and senescence markers (p16, p21) and Anti-miR-141-3p reversed the effect.

The decline in mitochondrial function during aging and associated disorders like neurodegeneration has received much attention, and there are extensive efforts underway to develop pharmacological treatments that can restore the potential and integrity of these crucial organelles. A large number of pharmacological modulators, both natural and synthetic, are being studied for their ability to reduce mitochondrial stress by targeting different pathways, including mitochondrial OXPHOS, ROS homeostasis, and metabolic processes. Furthermore, several other pathways, such as mitochondrial biogenesis, dynamics, and degradation, are also considered in developing therapeutics against mitochondria-associated disorders.

The depleted energy production by mitochondria due to various cellular stresses such as increased ROS levels and calcium dyshomeostasis, significantly affects energy-intensive cells like neurons. Scientists have explored various molecules that could potentially improve the functioning of the electron transport chain (ETC). For example, riboflavin and idebenone enhance the transfer of electrons, while others, such as thiamine and dichloroacetate, increase the availability of ETC substrates.

In addition, researchers have studied various natural compounds for their ability to regulate mitochondrial oxidative stress. For example, saponins derived from Panax japonicus and Panax notoginseng show neuroprotective effects by reducing mitochondrial damage through the induction of antioxidant responses. Besides this, several mitochondrial antioxidants, including MitoQ, Mitotempo, and Mito apocynin, protects mitochondria from oxidative damage.

Another approach to address energy deficiency involves increasing the number of mitochondria in cells by targeting transcription factors participating in formation of new mitochondria, such as PGC-1α. Pioglitazone, a type of thiazolidinedione, has been shown to have protective effects in several neurological diseases by targeting transcription factors such as PGC-1α. Furthermore, various studies show the protective effects of directly or indirectly activating mitochondrial biogenesis with compounds such as bezafibrate, resveratrol, and AICAR. It is evident that mitochondrial dynamics are altered in various neurodegenerative diseases, and different pharmacological interventions that can modulate the proteins involved in this process are investigated. Echinacoside (ECH) treatment shows neuroprotective effects by inducing mitochondrial fusion via increased transcription of Mfn2. Treatment with liquiritigenin, a flavonoid, has been found to induce mitochondrial fusion and protects against amyloid-β cytotoxicity.

Various modulators of mitophagy that have shown beneficial effects by removing damaged or altered mitochondria are identified. Urolithin A induces autophagic removal of altered mitochondria and extended lifespan in C. elegans. Spermidine treatment was found to induce both the mitophagy as well as biogenesis of mitochondria in aged mice heart cells. Metformin, a drug used in treating type 2 diabetes, has been found to enhance mitochondrial function by restoring ETC proteins and promoting mitophagy.

Both frailty and metabolic syndromes lead to the following consequences: poorer response to physical and/or mental stressors, increased risk of hospitalization, adverse outcomes, institutionalization and premature death. A similar pathogenesis underlies the development of the metabolic as well as the frailty syndrome in the context of oxidative stress and acceleration of inflammation. The disturbance of various metabolic processes on the cellular, tissue, and organ level have demonstrated that the syndromes represent two faces of the same coin.

Through the human lifespan, unfavorable biochemical phenomena accumulate, including increased inflammation and the progression of oxidative stress, which result in the manifestation of clinical dysfunctions and, as a result, premature death. Thus, aging is complicated by disorders such as decreased insulin sensitivity, hyperglycemia, hyperlipidemia or civilization diseases such as diabetes, hypertension, and cardiovascular diseases. Gathered clinical and metabolic conditions are seen in the metabolic syndrome. The main mechanism of pathology in the metabolic syndrome is insulin resistance.

Enhanced inflammation, increased reactive oxygen species (ROS) production and faint antioxidant defense systems are responsible for the improper synthesis, secretion and action of insulin leading to insulin resistance. Moreover, lower insulin sensitivity causes an imbalance toward muscle mass density, relative handgrip force, and decreased level of physical activity with an outcome of sarcopenia and thus leads to the clinical face of frailty syndrome. The aim of this narrative review is to pay attention to the interrelationships between the impact of inflammation, oxidative stress markers, and various metabolic pathways in the development of frailty and metabolic syndromes in elderly individuals, which underlie the pathogenesis of these syndromes.

T cells are critical in destroying cancer cells by recognizing antigens presented by MHC molecules on cancer cells or antigen-presenting cells. Identifying and targeting cancer-specific or overexpressed self-antigens is essential for redirecting T cells against tumors, leading to tumor regression. This is achieved through the identification of mutated or overexpressed self-proteins in cancer cells, which guide the recognition of cancer cells by T-cell receptors.

There are two main approaches to T cell-based immunotherapy: HLA-restricted and HLA-non-restricted immunotherapy. Significant progress has been made in T cell-based immunotherapy over the past decade, using naturally occurring or genetically engineered T cells to target cancer antigens in hematological malignancies and solid tumors. However, limited specificity, longevity, and toxicity have limited success rates.

This review provides an overview of T cells as a therapeutic tool for cancer, highlighting the advantages and future strategies for developing effective T cell cancer immunotherapy. The challenges associated with identifying T cells and their corresponding antigens, such as their low frequency, are also discussed. The review further examines the current state of T cell-based immunotherapy and potential future strategies, such as the use of combination therapy and the optimization of T cell properties, to overcome current limitations and improve clinical outcomes.

Thioredoxin and thioredoxin reductase are evolutionarily conserved antioxidant enzymes that protect organisms from oxidative stress. These proteins also play roles in redox signaling and can act as a redox-independent cellular chaperone. In most organisms, there is a cytoplasmic and mitochondrial thioredoxin system. The role of the cytoplasmic and mitochondrial thioredoxin systems in determining lifespan has been examined in multiple genetic model organisms through increasing or decreasing the expression of thioredoxin or thioredoxin reductase.

While there is evidence for a contribution of the thioredoxin systems to longevity in yeast, worms, flies, mice, and humans, the relative importance of each component of these systems varies between species. In yeast and C. elegans, disruption of the cytoplasmic thioredoxin system results in the largest detrimental effect on longevity, while disruption of the mitochondrial thioredoxin system has minimal impact on lifespan. In Drosophila, both the cytoplasmic and mitochondrial thioredoxin systems affect lifespan, with the largest effect observed with the cytoplasmic thioredoxin reductase.

In mice, both the cytoplasmic and mitochondrial thioredoxin systems are essential for life as disruption of any of the components results in embryonic lethality. Thus, it appears that in more complex organisms, there is a greater reliance on thioredoxin systems for survival and an increased importance of the mitochondrial thioredoxin system compared to less complex organisms.

While it is not possible to genetically manipulate the expression levels of thioredoxin system genes in humans, multiple studies have identified genetic variants that are associated with extended longevity. In a study comparing oldest-old individuals (age 92-93) with middle-aged individuals, an allele of the cytoplasmic thioredoxin reductase gene TXNRD1 was found to be associated with longevity. These results suggest that the thioredoxin system may also contribute to longevity in humans.

Age-related neurobiological changes significantly affect hippocampal structure and function, such that the main cognitive impairments associated with aging are related to the integrity of this brain structure, including the deterioration in spatial object recognition (SOR) memory. Previous studies have shown that intrinsic factors such as neuroinflammation, as well as lifestyle factors such as diet, can affect aging-associated brain functions and cognitive performance. In this regard, caloric restriction (CR) produces beneficial effects on health and life expectancy, although its ability to slow down age-dependent effects on cognitive decline and hippocampus (HPC) functioning remains unclear.

Therefore, we set out to evaluate the effects of CR on SOR memory in aged male Wistar rats, as well as those on hippocampal neuron loss, neurogenesis, and inflammation. The data show that CR in aged rats attenuates the decline in SOR memory, age-associated hippocampal neuron loss, and age-dependent microglial activation. Furthermore, we found a significant reduction in neurogenesis in the dentate gyrus of the old animals relative to adult rats. These findings support the positive effect of CR on SOR memory, suggesting that it dampens hippocampal neuronal loss and reduces proinflammatory activity.

Researchers worked with three groups of mice. Two groups were aged naturally side-by-side until they were 90 weeks old, which is similar to a 70-year-old person. At 90 weeks of age, both groups of old mice were evaluated for their cognitive abilities, such as remembering the correct route in a maze that leads to a food reward. These results were compared to those of young mice, the third group. Then, one group of old mice began a GlyNAC-supplemented diet, while the other group, called the old-controls, continued their regular diet without GlyNAC supplementation.

After completing eight weeks on their respective diets, the animals' cognitive abilities were evaluated again and their brains analyzed to measure specific brain defects that had previously been associated with cognitive impairment in studies by others. The results of these analyses in old mice supplemented with GlyNAC were compared with those of the old-control group and with the corresponding data obtained from young mice.

GlyNAC supplementation in old mice corrected brain glutathione deficiency, improved brain glucose transporters, reversed mitochondrial dysfunction and improved cognition. In addition, GlyNAC supplementation reduced oxidative stress, inflammation, and genomic damage and improved neurotrophic factors. Previous rodent studies reported that GlyNAC supplementation improved similar biological defects in the heart, liver and kidneys, and also increased length of life. A recently published randomized clinical trial in older humans provided evidence of similar improvements in skeletal muscle and blood and reversal of aging hallmarks.

We studied 308,156 UK Biobank participants with no history of cancer at enrollment. Using 18 age-associated clinical biomarkers, we computed three biological age measures (Klemera-Doubal method [KDM], PhenoAge, homeostatic dysregulation [HD]) and assessed their associations with incidence of any cancer and five common cancers (breast, prostate, lung, colorectal, and melanoma) using Cox proportional-hazards models.

A total of 35,426 incident cancers were documented during a median follow-up of 10.9 years. Adjusting for common cancer risk factors, 1-standard deviation (SD) increment in the age-adjusted KDM (hazard ratio = 1.04), age-adjusted PhenoAge (hazard ratio = 1.09), and HD (hazard ratio = 1.02) was significantly associated with a higher risk of any cancer. All biological age measures were also associated with increased risks of lung and colorectal cancers, but only PhenoAge was associated with breast cancer risk. Furthermore, we observed an inverse association between biological age measures and prostate cancer, although it was attenuated after removing glycated hemoglobin and serum glucose from the biological age algorithms.