Fight Aging! Newsletter, February 15th 2021

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative diseases. Currently, no cure is available although epidemiological studies suggest that the risk of developing neurodegenerative diseases can be modulated by lifestyle-related factors, suggesting that some cases could be prevented. The toxic accumulation, misfolding, or mis-localisation of proteins leading to neuronal loss, i.e. proteinopathies, are key pathological features of age-related neurodegenerative diseases.

Breakdown or removal of the proteins which are susceptible to form toxic aggregates is essential to prevent development of pathology. Many of these proteins, such as AD associated amyloid-β and tau and PD associated α-synuclein, are found in the cerebrospinal fluid (CSF). This raised the question of the significance of CSF for clearing toxic metabolites from the brain, and in 2012, the glial-lymphatic ("glymphatic") system, that describes a mechanism for brain clearance via a perivascular (also referred to as paravascular) CSF flow pathway was characterised. Indeed, the glymphatic system plays a role in clearance of amyloid-β, tau, and α-synuclein.

The glymphatic brain clearance mechanism relies on interchange of CSF and interstitial fluid (ISF) that allows waste to be transferred to the CSF and transported out of the brain. The system was named the glia-lymphatic or "glymphatic" system upon its discovery in 2012 as astrocyte end feet are a main structural component of the fluid exchange pathway. CSF is predominantly produced in the choroid plexus in the 3rd and lateral ventricles, and it is circulated from the ventricles to the subarachnoid space surrounding the brain primarily by arterial pulsations. The subarachnoid space is continuous with the periarterial spaces of the pial vessels, from which the CSF enters the brain parenchyma, where it facilitates the clearance of solutes, although the efflux routes are less described.

The interchange of CSF and ISF is dependent on aquaporin 4 (AQP4) water channels on astrocyte endfeet that enwrap the cerebral vasculature. Changes in AQP4 expression or polarisation - referring to the differential distribution of AQP4 in the endfeet versus rest of the cell - are associated with disturbances in glymphatic function. In line with the observation that the glymphatic system can clear amyloid-β, decreased glymphatic function caused by deletion of the Aqp4 gene in an animal model of Alzheimer's disease leads to increased accumulation of amyloid-β and tau. Abnormalities in AQP4 polarisation are also seen in Alzheimer's patients, which provides some evidence that glymphatic function might also play a role in Alzheimer's disease in humans.

Transthyretin (TTR) amyloidoses are under-recognized systemic diseases associated with TTR aggregation and extracellular deposition in tissues as amyloid. The most frequent and severe forms of the disease are hereditary and associated with amino acid substitutions in the protein due to single point mutations in the TTR gene (ATTRv amyloidosis). However, the wild type TTR (TTR wt) has an intrinsic amyloidogenic potential that, in particular altered physiologic conditions and aging, leads to TTR aggregation in people over 80 years old being responsible for the non-hereditary ATTRwt amyloidosis

The hallmark of ATTR amyloidosis is the extracellular deposition of aggregated TTR or TTR fibrils in tissues. The process of TTR aggregation and fibril formation is not completely elucidated, however biochemical and biophysical evidences indicate that the tetrameric form of TTR becomes unstable and the protein dissociates into dimers and monomers presenting a partially unfolded conformation which self-assemble into toxic non-fibrillar aggregates and, later into amyloid fibrils that accumulate as amyloid deposits throughout the body.

The mechanism by which the tetramer disassembles and aggregates into amyloid fibrils has been considered the main driver of the disease. However, TTR proteolysis, namely occurring in the cardiac tissue, as well as its modulation have been increasingly documented as fundamental for understanding the development and progression of ATTR amyloidosis.

Many therapeutic approaches have been suggested for the treatment of ATTR amyloidosis targeting different steps of the pathology. Those therapies include interventions from the synthesis of the TTR variants through liver transplant or gene silencing therapies and clearance of amyloid deposits. Additionally, several compounds have been suggested for the treatment of ATTR amyloidosis by targeting different steps of the amyloid formation. The main steps include TTR stabilization, inhibition of oligomerization, and fibril disruption.

Although some the available therapies are more efficient than others, it becomes increasingly evident that combination of different therapies may improve the therapeutic outcome. In this sense, it would be interesting to test TTR gene silencing therapies in combination with protein stabilizers or disruptors of pre-existing amyloid deposits.

The discovery and regulation of signals driving the aging process are long-standing goals in physiology. Aging negatively affects organ function. The description of the tissue-level age-associated changes in the literature remains restricted to the gross structural and tissue changes such as the increase in tissue stiffness and adiposity. In this study, we implement a large-scale 3D spatial comparison of vascular cells and molecules in young and aging mouse tissues from several organs to define the major changes across both axes. This in-depth analysis of aging tissues revealed vascular attrition as a primary hallmark of aging and provides unprecedented insights into the microenvironmental tissue-level changes during aging.

Our imaging datasets reveal that the loss of vascular abundance accompanied by the decline in pericytes is a key feature of aging tissues. This is the first comprehensive study highlighting age-dependent vascular changes across several organs. Loss of vessel density and pericytes emerges as the mark of aging organs and tissues; however, highly remodeling tissues with high regeneration potential, such as the skin, gut, and uterus, preserve the abundance of the blood vessels and pericytes with aging. Similarly, vessel densities remain unaffected in aging bones, which have relatively higher regeneration potential compared to tissues such as the kidney, spleen, heart, or brain. Thus, stage and extent of vascular attrition are likely to direct the regenerative limitations of a tissue.

Further, observations described herein corroborate the findings in injury-induced organ fibrosis where pericytes differentiate into fibroblasts to drive fibrosis. Our findings also demonstrate that pericytes are a source of fibroblasts in joint inflammation and that the differentiation of pericytes to fibroblasts increases with aging. Last, endothelial cell specific genetic manipulations prove that vascular loss drives cellular changes such as senescence. Together, these findings imply that the strategies to inhibit age-dependent changes in vasculature such as the loss of vascular abundance and pericyte to fibroblast differentiation have the potential to delay or even prevent cellular dysfunction during aging.

The force of natural selection is maximized during pre-reproductive development but declines after sexual maturation with advancing age. Therefore, mutations that have neutral or positive fitness effects early in life but negative fitness effects late in life can accumulate (mutation accumulation theory) or be selected for (antagonistic pleiotropy theory) in the population and lead to the evolution of ageing. While these ultimate population genetic theories of ageing are broadly accepted, the proximate routes that lead to ageing are still incompletely understood and subject to vigorous debate. The discovery of molecular signalling pathways that are evolutionarily conserved and regulate life-history traits, such as development, growth, reproduction, and lifespan showed that ageing is malleable, and sometimes can be modified by modulating the expression of a single gene that influences a large array of downstream physiological processes.

One proximate physiological account of the antagonistic pleiotropy theory, the disposability theory of ageing (DST), postulates that ageing and lifespan evolve as a result of optimized resource allocation between somatic maintenance and reproduction with the aim of maximizing reproductive output. This theory predicts that increased investment in somatic maintenance will increase survival at the cost of reduced reproduction, and vice versa, since they are assumed to compete for the same pool of resources. The predominance of this theory has been increasingly challenged in recent years. Studies in different model organisms have suggested that increased longevity and reduced reproduction can be uncoupled.

Nevertheless, researchers proposed a different mechanism underlying antagonistic pleiotropy, by suggesting that the declining force of selection with age can result in suboptimal levels of gene expression in late life. Because selection is strongest during development and declines after the onset of reproduction, selection can never fully 'optimize' age-specific gene expression resulting in ageing via the action of otherwise beneficial genes. This developmental theory of ageing (DTA) maintains that the decline in selection gradients with age results in suboptimal regulation of gene expression in adulthood, leading to cellular and organismal senescence.

There is an important distinction between these two physiological explanations of how antagonistically pleiotropic alleles work. The DST rests on the competitive allocation of resources between the body and the germline resulting in imperfect repair of cellular damage; this theory predicts that genetic and environmental manipulations that increase allocation to somatic maintenance (hence lifespan) result in reduced allocation to the immortal germline (hence reproduction). The DTA instead focuses on imperfect age-specificity of gene expression and predicts that optimizing gene expression in adulthood can improve somatic maintenance as well as the germline. Increased understanding of the evolutionarily conserved molecular pathways that control many different aspects of organismal life cycle allows direct testing of these two explanations. Since the DTA is based on the assumption that gene function affects fitness differently across the life course of the organism, perhaps the most straightforward way to test it is to modify the gene expression at different stages across the life course and assess the effects on fitness-related traits and on individual fitness.

Here we tested these predictions directly by modifying the age-specific expression of five well-described 'longevity' genes in Caenorhabditis elegans nematode worms that play key roles in different physiological processes: nutrient-sensing signalling via insulin/IGF-1 (age-1) and target-of-rapamycin (raga-1) pathways, global protein synthesis (ifg-1), global protein synthesis in somatic cells (ife-2), and mitochondrial respiration (nuo-6). Downregulation of these genes in adulthood and/or during post-reproductive period increases lifespan, while we found limited evidence for a link between impaired reproduction and extended lifespan. Our findings demonstrate that suboptimal gene expression in adulthood often contributes to reduced lifespan directly rather than through competitive resource allocation between reproduction and somatic maintenance. Therefore, age-specific optimization of gene expression in evolutionarily conserved signalling pathways that regulate organismal life histories can increase lifespan without fitness costs.

Aging is recognized as a common risk factor for many chronic diseases and functional decline. The newly emerging field of geroscience is an interdisciplinary field that aims to understand the molecular and cellular mechanisms of aging. Several fundamental biological processes have been proposed as hallmarks of aging. The proposition of the geroscience hypothesis is that targeting holistically these highly integrated hallmarks could be an effective approach to preventing the pathogenesis of age-related diseases jointly, thereby improving the health span of most individuals.

There is a growing awareness concerning the benefits of the prophylactic use of probiotics in maintaining health and improving quality of life in the elderly population. In view of the rapid progress in geroscience research, a new emphasis on geroscience-based probiotics is in high demand, and such probiotics require extensive preclinical and clinical research to support their functional efficacy. Here we propose a new term, "gerobiotics", to define those probiotic strains and their derived postbiotics and para-probiotics that are able to beneficially attenuate the fundamental mechanisms of aging, reduce physiological aging processes, and thereby expand the health span of the host.

We provide a thorough discussion of why the coining of a new term is warranted instead of just referring to these probiotics as anti-aging probiotics or with other similar terms. In this review, we highlight the needs and importance of the new field of gerobiotics, past and currently on-going research and development in the field, biomarkers for potential targets, and recommended steps for the development of gerobiotic products. Use of gerobiotics could be a promising intervention strategy to improve health span and longevity of humans in the future.

Age-related macular degeneration (AMD), a degenerative disease in the central macula area of the neuroretina and the supporting retinal pigment epithelium, is the most common cause of vision loss in the elderly. Although advances have been made, treatment to prevent the progressive degeneration is lacking. Besides the association of innate immune pathway genes with AMD susceptibility, environmental stress- and cellular senescence-induced alterations in pathways such as metabolic functions and inflammatory responses are also implicated in the pathophysiology of AMD.

Cellular senescence is an adaptive cell process in response to noxious stimuli in both mitotic and postmitotic cells, activated by tumor suppressor proteins and prosecuted via an inflammatory secretome. In addition to physiological roles in embryogenesis and tissue regeneration, cellular senescence is augmented with age and contributes to a variety of age-related chronic conditions. Accumulation of senescent cells accompanied by an impairment in the immune-mediated elimination mechanisms results in increased frequency of senescent cells, termed "chronic" senescence.

Age-associated senescent cells exhibit abnormal metabolism, increased generation of reactive oxygen species, and a heightened senescence-associated secretory phenotype that nurture a proinflammatory milieu detrimental to neighboring cells. Senescent changes in various retinal and choroidal tissue cells including the retinal pigment epithelium, microglia, neurons, and endothelial cells, contemporaneous with systemic immune aging in both innate and adaptive cells, have emerged as important contributors to the onset and development of AMD. The repertoire of senotherapeutic strategies such as senolytics, senomorphics, cell cycle regulation, and restoring cell homeostasis targeted both at tissue and systemic levels is expanding with the potential to treat a spectrum of age-related diseases, including AMD.

Using samples from the New England Centenarian Study (NECS), we sought to characterize the serum proteome of 77 centenarians, 82 centenarians' offspring, and 65 age-matched controls of the offspring (mean ages: 105, 80, and 79 years). We identified 1312 proteins that significantly differ between centenarians and their offspring and controls, and two different protein signatures that predict longer survival in centenarians and in younger people. By comparing the centenarian signature with two independent proteomic studies of aging, we replicated the association of 484 proteins of aging and we identified two serum protein signatures that are specific of extreme old age.

The data suggest that centenarians acquire similar aging signatures as seen in younger cohorts that have short survival periods, suggesting that they do not escape normal aging markers, but rather acquire them much later than usual. For example, centenarian signatures are significantly enriched for senescence-associated secretory phenotypes, consistent with those seen with younger aged individuals, and from this finding, we provide a new list of serum proteins that can be used to measure cellular senescence.

Protein co-expression network analysis suggests that a small number of biological drivers may regulate aging and extreme longevity, and that changes in gene regulation may be important to reach extreme old age. This centenarian study thus provides additional signatures that can be used to measure aging and provides specific circulating biomarkers of healthy aging and longevity, suggesting potential mechanisms that could help prolong health and support longevity.

A new review looks at the growing evidence to suggest that losing our 'old friend' helminth parasites, which used to live relatively harmlessly in our bodies, can cause ageing-associated inflammation. It raises the possibility that carefully controlled, restorative helminth treatments could prevent ageing and protect against diseases such as heart disease and dementia. "A decline in exposure to commensal microbes and gut helminths in developed countries has been linked to increased prevalence of allergic and autoimmune inflammatory disorders - the so-called 'old friends hypothesis'. A further possibility is that this loss of 'old friend' microbes and helminths increases the sterile, ageing-associated inflammation known as inflammageing."

Helminths have infected humans throughout our evolutionary history, and as a result have become master manipulators of our immune response. Humans, in turn, have evolved levels of tolerance to their presence. The loss of helminths has so far been linked to a range of inflammatory diseases, including asthma, atopic eczema, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and diabetes. Some studies have shown that natural infection with helminths can alleviate disease symptoms, for example in multiple sclerosis and eczema, while other studies in animal models suggest that intentional infection with helminths could have benefits against disease.

The safer, and perhaps more palatable, option is the concept of using helminth-derived proteins to achieve the same therapeutic benefits. This was tested recently in mice and shown to prevent the age-related decline in gut barrier integrity usually seen with a high-calorie diet. It also had beneficial effects on fat tissue, which is known to be a major source of inflammageing. The authors speculate that if helminths have anti-inflammageing properties, you would expect to see lower rates of inflammageing-related disease in areas where helminth infection is more common. There is some evidence to support this. "In the wake of successes during the last century in eliminating the evil of helminths, the time now seems right to further explore their possible benefits, particularly for our ageing population - strange as this may sound."

The goal of geroscience is extension of lifespan by extending healthspan. Standard medical interventions can prolong lifespan without extending healthspan (e.g., using a ventilator in comatose patient) but anti-aging interventions increase lifespan by slowing aging and thus delaying age-related diseases (extending healthspan). Healthspan is a period of life without age-related diseases. However, in comparison with lifespan, healthspan is difficult to measure, especially in animals. So why has healthspan become so popular in animal studies?

The reason is that only a few drugs were shown to extend lifespan in mammals. Other drugs seemingly increase healthspan but do not extend lifespan. This is considered an acceptable and even desirable effect. But it is not. Increased healthspan must automatically increase lifespan, if healthspan represents good health. Animals, including humans, do not die from good health, they die from age-related diseases. If diseases are delayed, an animal will live longer.

Consider a scenario in which lifespan is not increased, while healthspan is increased. To keep lifespan constant, while increasing healthspan, diseases must be compressed: start later but kill faster. For example, in this scenario, cancer kills an organism in a matter of minutes, instead of months. This is impossible. So how is it possible that some senolytics, NAD boosters, and resveratrol, increase healthspan without lifespan? The simplest explanation is that they do not increase healthspan at all, because such studies use irrelevant or ambiguous markers of health. Ambiguous parameters can be associated with either good or bad health, depending on the underlying cause. For example, similar changes in insulin signaling are associated with either slow or fast aging, depending on the mTOR activity.

Even if a drug does increase lifespan in mice and other mammals, gerontologists are still skeptical that it will work in humans. Consider an example. Calorie restriction (CR) extends lifespan in mice, rats and even monkeys. CR must extend lifespan in humans because it delays all age-related diseases in humans. Still it is debated whether it would extend life in humans. Some gerontologists think that it will not. Imagine, if CR would not increase lifespan in any mammal including mice. Would we then think that it may mysteriously extend life in humans? No. But then why are drugs that do not extend life in mice still being considered for the potential to extend life in humans? Although hundreds of recent reviews proclaim a wide arsenal of "emerging" drugs that "promise" to extend healthspan and lifespan, these drugs either do not extend lifespan in mice, or data is not sufficient.

There is an incredible diversity of body sizes and lifespans among living mammals, remarkably even larger mammals lived in the recent past but are now extinct. In living mammals, an individual's body size and lifespan are among the greatest predictors for the likelihood of developing cancer, taller and older humans, for example, have a greater cancer risk than shorter and younger people. Between species, however, body size and lifespan are poor predictors of cancer risk, thus big and long lived species must have evolved ways to reduce their risk of developing cancer. By understanding how big, long-lived species evolved their enhanced tumor suppression mechanisms we can improve our understanding of genes involved in human cancer and inspire new cancer treatments.

We tracked how body size and the copy number of most protein coding genes changed in elephants and their smaller bodied relatives. We found that as large bodied elephants evolved from smaller bodied ancestors, their cancer risk decreased. While genes involved in tumor suppression were commonly duplicated in elephants and their relatives, elephants have a unique repertoire of tumor suppressor genes that evolved alongside their recent increase in body size. These data show that duplication of tumor suppressor genes facilitated the evolution of large body size by compensating for increasing cancer risk.

"All of the greatest research programs start out with one scientist poking at something that he or she finds interesting. In this case it was the question of why mammalian cells do not routinely break down cholesterol, and instead make do with an intricate, fragile set of processes for shuttling cholesterol within cells and throughout the body. The presence of localized excesses of cholesterol in blood vessel walls is a lifespan-limiting circumstance that occurs to all of us, leading to atherosclerosis, then rupture or blockage of blood vessels that causes a stroke, heart attack, and death. Why then, do none of the cells involved in blood vessel tissue and the immune response to atherosclerosis actively break down cholesterol, but rather engage a Rube Goldberg apparatus of moving cholesterol around to try to solve the problem? The reason why we have atherosclerosis in the first place is that this machinery fails the moment that the tissue environment departs from a youthful, undamaged ideal. It is not robust at all. A more direct approach is needed."

The core mechanisms of CDP came into being due to the academic curiosity of a few "visionary and talented researchers"; once a way to safely break down excess cholesterol in cells was found and optimised, the Strategies for Engineered Negligible Senescence (SENS) community, who are focused on producing effective treatments for aging and age-related disease, became aware of these mechanisms and worked on implementing CDP. "The scientists presented their data at the first Undoing Aging conference, and Aubrey de Grey of the SENS Research Foundation later made an introduction to Repair Biotechnologies. The SENS philosophy - and the Repair Biotechnologies philosophy - is to reverse age-related disease by repairing the damage that causes it. Excess cholesterol is clearly a form of damage. Removing it is a form of repair. CDP strikes at a root cause of atherosclerosis, and other conditions in which excess cholesterol drives pathology. That makes it very attractive to those of us who think of aging in terms of damage and think of rejuvenation in terms of repair."

CDP is a platform technology that seeks to solve the root cause of cholesterol build-up by degrading excess, non-essential cholesterol with an entirely new, target-specific, rate-limited pathway, which the process introduces into cells. "We introduce a de novo pathway for catabolism of excess cholesterol, breaking it down into a water-soluble catabolite that leaves cells and is removed from the body fairly rapidly. Introduced into mice, the CDP pathway is safe and well-tolerated. It does not interfere with the normal cholesterol metabolism required for cellular activities. It is a very attractive basis for therapy."

Despite time, energy and money being poured into age-related disease research around the world, humans are yet to find cures for illnesses such as Alzheimer's, cardiovascular disease, and diabetes. SENS Research Foundation believes this is because current research is approaching the problem from the wrong angle.

Our vision is a world in which people do not decline in physical or mental health as they get older. We believe it is possible to create medicines that will restore the molecular and cellular structure and composition of the body of a middle-aged (or older) person to something like it was when they were a young adult. That amounts to repairing the damage that has accumulated in their bodies as intrinsic side-effects of the body's normal operation. We have known for decades what types of damage there are that eventually contribute to the health problems of late life; therefore, all (!) that is needed is to develop damage-repair therapies that can eliminate them. And that's what we do. The development of some of those therapies has progressed far enough that we have been able to spin the projects out as startup companies, and it's likely that most of them will be in the clinic within a couple of years.

SENS relates to all the types of damage we accumulate, and it does not take a position concerning which type of damage is more important than which other type. The right way to describe what SENS is is that it is an engineering proposal for how to manipulate nature, rather than a scientific hypothesis for how nature works in the first place. The Foundation's strategy to prevent and reverse age-related ill-health is to apply the principles of regenerative medicine to repair the damage of aging at the level where it occurs. We are developing a new kind of medicine: regenerative therapies that remove, repair, replace, or render harmless the cellular and molecular damage that has accumulated in our tissues with time. By reconstructing the structured order of the living machinery of our tissues, these rejuvenation biotechnologies will restore the normal functioning of the body's cells and essential biomolecules.

At our Research Center we have two main projects right now. One is devoted to repairing mutant mitochondria, by inserting genes into cells that will provide the proteins that the mitochondria can no longer make. The other project is exploring two new ways to eliminate senescent cells, cells that have switched into a damaging state and that the body wants to kill off but cannot. We also rent out space to one of our spin-out companies, Underdog Pharmaceuticals, which is developing a way to extract the oxidised cholesterol from arteries and thereby revert atherosclerosis (a disease of the arteries characterised by the deposition of fatty material on their inner walls). We are always reviewing our range of projects, and we may have a new project starting in a couple of months that will explore the elimination of a particular type of waste product in the brain.

Mitochondria play a key role in the production of energy and balance of reactive oxygen species (ROS) within cells. Mitophagy, the selective breakdown and clearance of aberrant and dead mitochondria, is a regulatory process essential to promoting cellular health and maintaining healthy mitochondrial populations. As a person age, oxidative stress and cellular damage accumulate, and autophagic pathways can become overwhelmed. This is especially true in non-actively dividing cells such as neurons, and cortical degeneration is commonly observed in aging populations.

Alzheimer's disease (AD), a characteristic illness of aging, is associated with cognitive deficits, including loss of memory formation and increased loss of cortical mass. Furthermore, characteristic conglomerates of amyloid-β (Aβ) and fibrillary tangles of abnormally phosphorylated tau are observed within the brains of AD patients. Synaptic damage and defective mitophagy are early changes in disease progression, and aging plays a key role in synaptic damage, autophagy, and mitophagy in AD progression and pathogenesis.

In the past 20 years, the toxicity of these mechanisms has been studied extensively, and their role in neuronal death partially elucidated. The buildup of abnormal mitochondria is noted in AD neurons. More recently, studies have focused on the interaction between Aβ and tau on the components of mitophagy. Although some interactions between Aβ and tau and also Aβ and tau interactions with mitochondrial proteins and the components of mitophagy have been noted; the exact mechanisms and sequence of events leading to the genesis of AD have yet to be elucidated. Accumulation of damaged mitochondria, excessive mitochondrial fission, the buildup of ROS within cells, and compromised cellular health are all noted within neuronal populations in AD brains.

A major challenge in studies on the pathology of AD is identifying individuals with early-onset AD as the symptoms mimic what is normally expected in aging populations. Identification of the early events of AD within these populations can help elucidate the development of biomarkers and pathology in AD and outline the mechanisms by which symptoms occur. Further research could potentially develop mitophagy-based therapies to block or even reverse the adverse effects of AD.

DNA methylation is one of the key mechanisms thought to underlie the association between aging and cancer. Biological aging measures derived from blood DNA methylation - taking advantage of varying rates of aging-associated methylation changes between individuals - have gained considerable popularity as tools to better understand and predict disease. We previously investigated the association between 5 "first-generation" measures of epigenetic aging and the risk of 7 cancer types using data from the Melbourne Collaborative Cohort Study (MCCS). The observed associations were relatively weak compared with those obtained for all-cause mortality; cancer risk overall was increased by 4%-9% per 5-year increase in methylation "age acceleration," although these estimates varied by cancer type.

Two novel methylation-based measures of biological aging, called PhenoAge and GrimAge, have been developed based on associations of DNA methylation with, for PhenoAge, age, mortality, and clinical biomarkers; and for GrimAge, smoking pack-years and plasma concentrations of adrenomedullin, beta-2 microglobulin, cystatin C, growth differentiation factor 15, leptin, plasminogen activation inhibitor 1, and tissue inhibitor metalloproteinase 1. These new measures have proved to be more strongly associated with mortality than the first-generation measures. This study assessed cancer risk associations for 3 recently developed methylation-based biomarkers of aging: PhenoAge, GrimAge, and predicted telomere length.

We observed relatively strong associations of age-adjusted PhenoAge with risk of colorectal, kidney, lung, mature B-cell, and urothelial cancers. Similar findings were obtained for age-adjusted GrimAge, but the association with lung cancer risk was much larger, after adjustment for smoking status, pack-years, starting age, time since quitting, and other cancer risk factors. Most associations appeared linear, larger than for the first-generation measures, and were virtually unchanged after adjustment for a large set of sociodemographic, lifestyle, and anthropometric variables.

Senescent cells accumulate in organs during aging, promote tissue dysfunction, and cause numerous aging-related diseases like cancer. The cells arise through a process called "cellular senescence," a permanent cell cycle arrest resulting from multiple stresses. Researchers have identified an inhibitor of the glutamate metabolic enzyme GLS1 so that its administration selectively eliminates senescent cells in vivo. They confirmed that the GLS1 inhibitor eliminated senescent cells from various organs and tissues in aged mice, ameliorating age-associated tissue dysfunction and the symptoms of obese diabetes, arteriosclerosis, and NASH.

The research team has developed a new method for producing purified senescent cells to search for genes essential for senescent cells' survival. This new method activates the p53 gene in the G2 phase, which can efficiently induce cellular senescence. They used purified senescent cells to search for genes essential for senescent cells' survival, then identified GLS1, which is involved in glutamine metabolism, as a potential candidate gene.

When they examined the effect of GLS1 inhibition on the mortality of senescent cells, senescent cells were more sensitive to GLS1 inhibition due to damage to the lysosomal membrane and decreased intracellular pH. The organelles called lysosomes play an essential role in the regulation of intracellular pH. The team analyzed the dynamics of lysosomes and found the vital fact that damage to the lysosomal membranes in senescent cells lowers intracellular pH. When they administered GLS1 inhibitors to aged mice, senescent cells in various tissues and organs were removed, and the aging phenomenon was significantly improved.