Fight Aging!

There are many different ways to conceptualize programs of research and development aimed at the treatment of aging. The Strategies for Engineered Negligible Senescence (SENS) is focused on aging as damage accumulation, and treatment is thus damage repair: remove senescent cells, restore mitochondrial function, clear out harmful protein aggregates, and so forth. Programmed aging viewpoints instead focus on ways to alter what are suspected to be evolved programs that drive aging, with this line of thought most often centered around the reversal of epigenetic changes that are observed to occur with age.

In today's open access paper, the authors propose a viewpoint that they call juventology, the study of youth, in analogy to gerontology, the study of aging. Clearly calorie restriction and related interventions adjust the operation of metabolism to slow aging and prolong the period of youthful life in many species. This might be taken as the existence of youth-maintaining programs, a delay of aging programs, or a slowing of damage accumulation. People tend to see their own view of aging reflected in the data for calorie restriction. It causes such a broad set of changes in cellular biochemistry, where that biochemistry is itself not fully mapped, that it is hard to mount arguments in support of one theory of aging versus another.

Is this really a good choice of strategy, however? Do we believe that calorie restriction is a starting point for a field that will in time engineer some form of altered metabolism that is far more effective when it comes to prolonging youthful life? In principle this has to be the case, as similar species with radically different life spans exist in the wild. Compare mice with naked mole-rats, for example, a nine-fold difference in life expectancy. In practice, I suspect that engineering human cellular metabolism to this degree is a far future prospect, however. The advantage of the damage repair approach is that it does seem to offer goals that can be achieved in the near future, without a full understanding of cellular biochemistry, and which will achieve meaningful gains in life span and reduction in the burden of age-related disease.

Exploring juventology: unlocking the secrets of youthspan and longevity programs

The paradigm of longevity programs opens up new vistas for understanding interventions that extend lifespan without instigating adverse effects. While traditional aging research has often fixated on combating free radicals and oxidative stress, juventology suggests that the most effective pro-longevity interventions induce alternate survival phases. The exploration of longevity programs in model organisms reveals a complex network of cellular responses and adaptive strategies that challenge the somewhat conventional theories of aging. Especially, the interplay between nutrient availability and the activation of specific longevity programs is not just a passive response but instead highlights a sophisticated network of cellular events that over the course of the lifespan can result in a healthier aging phenotype and increased longevity. In E. coli, Saccharomyces cerevisiae, and C. elegans, starvation, the most severe form of dietary restriction, causes a major lifespan extension.

Juventology is fundamentally different from "aging-centered" theories of aging for two reasons: (1) alternative lifespan programs, such as those entered in response to starvation, can be independent (or are at least partially independent) of aging itself. As an example, one could visualize the use of target-specific pharmaceuticals or systemically broader acting periodic fasting intervals modulate the mTor-S6K and PKA pathways, which in turn can promote regeneration and rejuvenation. Notably, this can be achieved even in an organism with a high rate of aging. Thus, even in an accelerated aging phenotype, a longer healthspan and lifespan may be accomplished by periodically activating regenerative and rejuvenating processes. (2) Juventology shifts the focus from an "old or older age" paradigm characterized by high degrees of dysfunction and subsequent high morbidity and mortality, instead to the period in life during which both morbidity and mortality are very low and only difficult to detect.

Diseases in humans are generally rare before the (biological) age 40, but comorbidities are common after age 65, yet no specific field of science is focusing on how evolution resulted in a program that is extremely efficient in preventing disease for the first 40 years of life and how that program may be modulated and extended by dietary, pharmacological, or other interventions. On the one hand, developmental biology focuses on the biological process from embryo to (young) adult stage and generally does not include this important field. On the other hand, biogerontology the biological basis of aging and age-related diseases. Thus, juventology presents a complementary field to both gerontology and developmental biology that focuses on the period of organismal life when the force of natural selection is high and body functions remain maximized.

Periodic fasting and calorie restriction promote cells to enter into a stress resistance state which is characterized by the activation of cell protection, regeneration, and rejuvenation processes. Across multiple species, these protective and regenerative mechanisms are activated in part by the down-regulation of growth hormone, IGF-1, mTor-S6K, and PKA signaling cascades, which in turn induces the extension of healthspan. Because these states have evolved to withstand periods of extreme nutrient starvation, they can be viewed as alternative longevity programs activated to maintain cellular "youthspan" until resources that promote proliferative processes become available again. Here, we propose that these juventology-based approaches provide complementary strategies to the classic biogerontology approaches to focus on the earlier (i.e., biologically younger) functional period while also studying the later progressively dysfunctional processes that affect health and longevity.

Researchers here demonstrate an approach to cell therapy for an injured heart that produces lesser degrees of abnormal function than prior efforts. There has been some concern that delivering new cells to the heart to spur greater regeneration will disrupt the electrical regulation of heartbeats, as animal studies suggested an unacceptable risk of arrhythmia following treatment. This work still makes use of cardiomyocytes generated from induced pluripotent stem cells, already accomplished by a number of other groups, but differences in the details of the approach appear to make a positive change in the outcome.

In a recent study, a research team tested a new strategy for regenerative heart therapy that involves injecting 'cardiac spheroids' derived from human induced pluripotent stem cells (HiPSCs) into monkeys with myocardial infarction. First, the team verified the correct reprogramming of HiPSCs into cardiomyocytes. They observed, via cellular-level electrical measurements, that the cultured cells exhibited potential patterns typical of ventricular cells. The cells also responded as expected to various known drugs. Most importantly, they found that the cells abundantly expressed adhesive proteins such as connexin 43 and N-cadherin, which would promote their vascular integration into an existing heart. Afterwards, the cells were transported from the production facility. The cardiac spheroids, which were preserved at 4°C in standard containers, withstood the four-hour journey without problem. This means that no extreme cryogenic measures would be needed when transporting the cells to clinics, which would make the proposed approach less expensive and easier to adopt.

Finally, the monkeys received injections of either cardiac spheroids or a placebo directly into the damaged heart ventricle. During the observation period, the researchers noted that arrythmias were very uncommon, with only two individuals experiencing transient tachycardia (fast pulse) in the first two weeks among the treatment group. Through echocardiography and computed tomography exams, the team confirmed that the hearts of monkeys that received treatment had better left ventricular ejection after four weeks compared to the control group, indicating a superior blood pumping capability. Histological analysis ultimately revealed that the cardiac grafts were mature and properly connected to pre-existing existing tissue. "The favorable results obtained thus far are sufficient to provide a green light for our clinical trial. We are already employing the same cardiac spheroids on patients with ischemic cardiomyopathy."

Link: https://www.shinshu-u.ac.jp/english/topics/2024/04/using-stem-cell-deri.html

While researchers here focus specifically on stair climbing as a form of physical activity to compare against risk of mortality in later life, there are any number of other studies that focus on activity more generally, or on other forms of moderate to vigorous exercise. The consensus across epidemiological studies is that physical activity correlates with reduced mortality. Animal studies have been used to demonstrate that the exercise in fact causes that reduced mortality, and it is reasonable to consider that the same is true in humans.

Cardiovascular disease is largely preventable through actions like exercise. However, more than one in four adults worldwide do not meet recommended levels of physical activity. Stair climbing is a practical and easily accessible form of physical activity which is often overlooked. This study investigated whether climbing stairs, as a form of physical activity, could play a role in reducing the risks of cardiovascular disease and premature death.

The authors collected the best available evidence on the topic and conducted a meta-analysis. Studies were included regardless of the number of flights of stairs and the speed of climbing. There were nine studies with 480,479 participants in the final analysis. The study population included both healthy participants and those with a previous history of heart attack or peripheral arterial disease. Ages ranged from 35 to 84 years old and 53% of participants were women.

Compared with not climbing stairs, stair climbing was associated with a 24% reduced risk of dying from any cause and a 39% lower likelihood of dying from cardiovascular disease. Stair climbing was also linked with a reduced risk of cardiovascular disease including heart attack, heart failure, and stroke.

Link: https://www.eurekalert.org/news-releases/1042193

Atherosclerosis is the growth of fatty lesions in blood vessel walls, ultimately leading to a heart attack or stroke when an unstable lesion ruptures. Atherosclerosis is primarily a condition of macrophage dysfunction, in which these cells fail to keep up with their task of removing excess cholesterol from blood vessel walls in order to return it to to the bloodstream for transport back to the liver. The local excess of cholesterol is largely the proximate cause of this macrophage dysfunction, so as the amount of cholesterol grows, macrophages become ever less capable of dealing with it. They die, adding their mass to the lesion, while signaling for reinforcements that will suffer the same fate.

That said, this is a description of how atherosclerosis progresses once it gets started. How do the initial small excesses of cholesterol form in the first place? Most of the underlying root causes of aging are involved in the growing inability of macrophages to keep up with the task of cholesterol transport. Further, altered behavior of other cell populations with advancing age, in the liver and blood vessel walls, may be capable of disrupting cholesterol transport from the liver to the rest of the body, leading to excess deposits in blood vessels. In today's open access paper, researchers focus in on the age-related decline in mitochondrial function in the context of atherosclerosis: would improving mitochondrial function help?

Effects of mitochondrial dysfunction on cellular function: Role in atherosclerosis

Atherosclerosis is the basis of a large proportion of fatal cardiovascular events, and a significant number of cardiovascular-related deaths can be attributed to the rupture of atherosclerotic plaques. Thinning of the covered fibrous cap formed by vascular smooth muscle cells (VSMCs) results in cap rupture and erosion, which is responsible for the majority of cardiovascular-related deaths from myocardial infarction and stroke. Atherosclerosis is an age-associated disorder; however, with the development of non-invasive diagnostic methods and the accumulation of knowledge in postmortem research, asymptomatic lesions have been described in young adults, suggesting that atherosclerosis is a chronic disease that develops at a much younger age than previously thought.

Atherosclerosis is now widely accepted to begin with endothelial dysfunction and lipid deposits, which progress through macrophage infiltration. In atherosclerosis-prone areas, the chronic inflammatory response and impaired lipoprotein metabolism are among the major contributors to atherosclerotic lesion formation. The first idea linking mitochondria to atherosclerosis was reported in 1970, but it is only recently that increasing evidence has highlighted the key role of mitochondrial dysfunction in the pathogenesis of atherosclerosis. Mitochondrial dysfunction can induce high levels of oxidative stress and high rates of apoptosis, which can cause endothelial dysfunction and increase the vascular disease burden. The increase in reactive oxygen species (ROS) production in mitochondria, accumulation of mitochondrial DNA damage, and progressive respiratory chain dysfunction are all related to atherosclerosis.

Mitochondrial dysfunction is believed to result in an increase in reactive oxygen species, leading to oxidative stress, chronic inflammation, and intracellular lipid deposition, all of which can contribute to the pathogenesis of atherosclerosis. Critical cells, including endothelial cells, vascular smooth muscle cells, and macrophages, play an important role in atherosclerosis. Mitochondrial function is also involved in maintaining the normal function of these cells. To better understand the relationship between mitochondrial dysfunction and atherosclerosis, this review summarizes the findings of recent studies and discusses the role of mitochondrial dysfunction in the risk factors and critical cells of atherosclerosis.

The author of this paper is an advocate for programmed aging. This is the view that degenerative aging is actively selected by evolutionary processes, perhaps because it helps to reduce the risk of runaway population growth, or perhaps because aging species better adapt to ecological change, rather than being a side-effect of selection effects focused on early life reproductive success that tend to produce systems that accumulate damage to fail over time. In some programmed aging views, epigenetic change is close to being the root cause of aging, being the implementation of an evolutionarily selected program. It is interesting to see an outline of perceived challenges in epigenetic clock development from the programmed aging viewpoint, to contrast with the challenges seen by other researchers, which are focused on the lack of understanding of how specific epigenetic changes reflect underlying damage and dysfunction.

Late in life, the body is at war with itself. There is a program of self-destruction (phenoptosis) implemented via epigenetic and other changes. I refer to these as type (1) epigenetic changes. But the body retains a deep instinct for survival, and other epigenetic changes unfold in response to a perception of accumulated damage (type (2)).

In the past decade, epigenetic clocks have promised to accelerate the search for anti-aging interventions by permitting prompt, reliable, and convenient measurement of their effects on lifespan without having to wait for trial results on mortality and morbidity. However, extant clocks do not distinguish between type (1) and type (2). Reversing type (1) changes extends lifespan, but reversing type (2) shortens lifespan. This is why all extant epigenetic clocks may be misleading.

Separation of type (1) and type (2) epigenetic changes will lead to more reliable clock algorithms, but this cannot be done with statistics alone. New experiments are proposed. Epigenetic changes are the means by which the body implements phenoptosis, but they do not embody a clock mechanism, so they cannot be the body's primary timekeeper. The timekeeping mechanism is not yet understood, though there are hints that it may be (partially) located in the hypothalamus. For the future, we expect that the most fundamental measurement of biological age will observe this clock directly, and the most profound anti-aging interventions will manipulate it.

Link: https://doi.org/10.1134/S0006297924020135

The progressive dysfunction of sweat glands in the skin is probably not high on the list of items that people think about in the context of degenerative aging, at least not until they experience it. A reduced capacity of sweat glands leads to heat intolerance, and it is one of the contributing causes of the raised mortality rate among the elderly in heat waves. Here, researchers examine some of the biochemistry of sweat gland cells in aging mice. They focus in on a number of proteins that may turn out to be viable targets for drugs to force sweat glands in aged skin back to a more youthful degree of function. It is a long road from fundamental investigations of this sort to that outcome, however.

Evaporation of sweat on the skin surface is the major mechanism for dissipating heat in humans. The secretory capacity of sweat glands (SWGs) declines during aging, leading to heat intolerance in the elderly, but the mechanisms responsible for this decline are poorly understood. We investigated the molecular changes accompanying SWG aging in mice, where sweat tests confirmed a significant reduction of active SWGs in old mice relative to young mice.

We first identified SWG-enriched messenger RNAs (mRNAs) by comparing the skin transcriptome of Eda mutant Tabby male mice, which lack SWGs, with that of wild-type control mice by RNA-sequencing analysis. This comparison revealed 171 mRNAs enriched in SWGs, including 47 mRNAs encoding 'core secretory' proteins such as transcription factors, ion channels, ion transporters, and trans-synaptic signaling proteins. Among these, 28 SWG-enriched mRNAs showed significantly altered abundance in the aged male footpad skin, and 11 of them, including Foxa1, Best2, Chrm3, and Foxc1 mRNAs, were found in the 'core secretory' category.

Consistent with the changes in mRNA expression levels, immunohistology revealed that higher numbers of secretory cells from old SWGs express the transcription factor FOXC1, the protein product of Foxc1 mRNA. In sum, our study identified mRNAs enriched in SWGs, including those that encode core secretory proteins, and altered abundance of these mRNAs and proteins with aging in mouse SWGs.

Link: https://doi.org/10.18632/aging.205776

Robust modern forms of vaccination that were developed in the 20th century remain one of the most important forms of medical technology. Infectious diseases are not going away any time soon, and continue to cause a sizable fraction of human mortality, even though that fraction is much reduced in our era. Unfortunately, effective vaccination depends on an effective immune system, and thus vaccines tend to perform increasingly poorly with advancing age. As we age our immune system becomes ever less capable, a decline into immunosenescence caused by a range of contributing processes: involution of the thymus, where T cells of the adaptive immune system mature; a growing presence of senescent, exhausted, and malfunctioning immune cells; a shift in cell populations of the bone marrow to produce more myeloid and fewer lymphoid cells; and so forth.

As today's open access paper points out, the approach to improving vaccination in the old has long been to find ways to work around the growing incapacity of the aged immune system. Developing better adjuvants to vaccines, for example. This produces only incremental gains. The yearly toll of influenza deaths is much larger than the estimates of prevented deaths due to widespread vaccination. For the 2022-2023 season those numbers show 21,000 estimated deaths versus 3,600 estimated prevented deaths. Most of those deaths are old people, not only less able to defend against an infectious pathogen, but also less able to benefit from vaccination. Something must change! That change must be to focus on ways to repair the aged immune system, restore its function to more youthful capabilities.

There are any number of approaches presently under development that show promise. Restoration of active thymic tissue would help by providing a supply of new T cells. Use of CASIN can produce lasting improvements in hematopoietic stem cell function in the bone marrow following a single treatment. Clearance of populations of malfunctioning immune cells has been demonstrated to improve immune function in animal models. Clearance of senescent cells can reduce the burden of unresolved inflammatory signaling that puts stress on the aged immune system. There are more in various stages of development.

Insights into vaccines for elderly individuals: from the impacts of immunosenescence to delivery strategies

The global population is entering an era of aging. Older people are more susceptible to pathogens and have higher rates of morbidity and mortality. Despite the significant success of current vaccine products, many commercial vaccines fail to generate effective and long-lasting immune protection in elderly individuals. With increasing age, the reasons for the decline in vaccine potency are multifactorial. Age-related dysregulation of lymph nodes, and crucial immune cells jointly reduces the efficiency of vaccination. With the continuous emergence of new pathogens, it is urgent to create strategies to improve vaccination-mediated protection for elderly individuals.

The existing approaches are primarily aimed at optimizing the vaccine delivery system rather than inhibiting the immunosenescence of the immune microenvironment in elderly individuals. Inhibiting the immunosenescence of elderly individuals can evoke strong and long-lasting immune protection, which serves as a critical measure to improve vaccine-induced immunity. Although inhibition of immunosenescence most likely requires continuous intervention/treatment and is complicated to achieve, we believe that sustained-release vaccination/adjuvants or booster immunizations may sustainably ameliorate immunosenescence in the elderly. Once the immunosenescence of the elderly is corrected, their immune efficacy against various antigens can be improved.

An attractive research direction will be discovering immunomodulators and vaccine formulations that can inhibit immunosenescence. The selection of adjuvants can greatly impact the type and magnitude of the immune response. Considering the special immune status of elderly individuals, designing tailored vaccine adjuvants is indispensable for the development of next-generation vaccines for older individuals. A chronic inflammatory state also accompanies immunosenescence. However, the common opinion is that adjuvants promote immunity by inducing local inflammation. Therefore, more in-depth studies are needed to explain the role of inflammation in vaccine-induced immunity and tune the contradictory perspectives.

Most studies focus on one or several cell types or certain processes of the immune response. However, our immune system is a complex and coordinated comprehensive network. More new technologies and advances will help reveal the complexity underlying the human immune system. We must pay more attention to the impacts of versatile cells or multiple immune cascade processes. Future research should focus on developing scientific methods to build more convincing models of aging and study the profound mechanisms underlying age-related alterations that impact the immune responses of older people.

One the important themes of the research and development at Repair Biotechnologies is that localized excesses of cholesterol arise with age, leading to excess intracellular cholesterol, which is a pathological mechanism that disrupts cell behavior and kills cells. Getting rid of these localized excesses of cholesterol is challenging, however, unless resorting to some form of engineered protein machinery or gene therapy. Cells cannot break down cholesterol and there is no good way to bind enough of the excess cholesterol to some form of small molecule for sequestration and disposal without also targeting vital cholesterol in cell membranes and elsewhere. As this paper notes, excess cholesterol is clearly a meaningful problem in aging.

Although dysregulated cholesterol metabolism predisposes aging tissues to inflammation and a plethora of diseases, the underlying molecular mechanism remains poorly defined. Here, we show that metabolic and genotoxic stresses, convergently acting through liver X nuclear receptor, upregulate CD38 to promote lysosomal cholesterol efflux, leading to nicotinamide adenine dinucleotide (NAD+) depletion in macrophages. Cholesterol-mediated NAD+ depletion induces macrophage senescence, promoting key features of age-related macular degeneration (AMD), including subretinal lipid deposition and neurodegeneration.

NAD+ augmentation reverses cellular senescence and macrophage dysfunction, preventing the development of AMD phenotype. Genetic and pharmacological senolysis protect against the development of AMD and neurodegeneration. Subretinal administration of healthy macrophages promotes the clearance of senescent macrophages, reversing the AMD disease burden. Thus, NAD+ deficit induced by excess intracellular cholesterol is the converging mechanism of macrophage senescence and a causal process underlying age-related neurodegeneration.

Link: https://doi.org/10.1016/j.celrep.2024.114102

Improved autophagy is implicated in many of the approaches shown to slow aging in animal models. An open question is whether more targeted approaches to altering the regulation of autophagy in aged cells can improve matters to a greater degree than, for example, exercise or the practice of calorie restriction, both of which are known to produce general improvements in autophagy. Researchers here show that improvement of autophagy via increased expression of TRP53INP2 in old mice can reduce the age-related loss muscle mass and function that leads to sarcopenia. It seems an interesting target for further development of therapies.

Sarcopenia is a major contributor to disability in older adults, and thus, it is key to elucidate the mechanisms underlying its development. Increasing evidence suggests that impaired macroautophagy/autophagy contributes to the development of sarcopenia. However, the mechanisms leading to reduced autophagy during aging remain largely unexplored, and whether autophagy activation protects from sarcopenia has not been fully addressed.

Here we show that the autophagy regulator TP53INP2/TRP53INP2 is decreased during aging in mouse and human skeletal muscle. Importantly, chronic activation of autophagy by muscle-specific overexpression of TRP53INP2 prevents sarcopenia and the decline of muscle function in mice. Acute re-expression of TRP53INP2 in aged mice also improves muscle atrophy, enhances mitophagy, and reduces reactive oxygen species (ROS) production. In humans, high levels of TP53INP2 in muscle are associated with increased muscle strength and healthy aging. Our findings highlight the relevance of an active muscle autophagy in the maintenance of muscle mass and prevention of sarcopenia.

Link: https://doi.org/10.1080/15548627.2024.2333717

The Targeting Aging with Metformin (TAME) clinical trial has been a feature of the divide between regulators, researchers, and industry in the matter of treating aging as a medical condition for as about as long as the longevity industry has existed. Regulators such as the FDA do not consider aging to be a disease, and they only approve treatments for specific diseases, largely using the World Health Organization's International Classification of Diseases as the basis for what is and is not a disease. The TAME trial came into being as a way to convince the FDA to approve a treatment on the basis of endpoints that approximated aging, rather than a disease.

In that sense the heavy lifting has been accomplished: the FDA indeed agreed with the TAME trial design, and so in principle anyone else with deep pockets could now adopt the same approach if they wanted to stand behind a treatment for aging. The biotech industry and those who fund it are highly conservative, however. Companies working on therapies that can in principle slow or reverse aspects of aging have all chosen to pick one or more specific age-related diseases, and quietly plan for off-label use following approval, as it is unlikely that they could otherwise have convinced investors to back their clinical and regulatory development.

As today's popular science article notes, the TAME trial remains incompletely funded. This, I suspect is the case in large part because metformin is a poor choice of treatment. It was selected because it is so very widely used, for so long, and with such an abundance of safety data, that the FDA could not possibly object on those grounds. Hindsight is 20/20, but rapamycin would be been a much better choice. The evidence for metformin to slow aging is not great. The animal data is mixed, to say the least, and the human data from studies of type 2 diabetes patients has a great many issues. Rapamycin more clearly slows aging, the animal data is robust, and human evidence shows minimal to no side-effects at the dose for anti-aging use. Still, here we are: it remains unclear as to whether the TAME trial will be completed, or be overtaken by events. The evolution of regulation with regards to the treatment of aging will likely shift to a battle over widespread off-label use as the first longevity industry therapies are approved for specific disease.

A cheap drug may slow down aging. A study will determine if it works

Metformin was first used to treat diabetes in the 1950s in France. The FDA approved metformin for the treatment of type 2 diabetes in the U.S. in the 1990s. Since then, researchers have documented several surprises, including a reduced risk of cancer. As promising as this sounds, most of the evidence is observational, pointing only to an association between metformin and the reduced risk. The evidence stops short of proving cause and effect. Also, it's unknown if the benefits documented in people with diabetes will also reduce the risk of age-related diseases in healthy, older adults.

Back in 2015, a bunch of aging researchers began pushing for a clinical trial. "A bunch of us went to the FDA to ask them to approve a trial for metformin, and the agency was receptive. If you could help prevent multiple problems at the same time, like we think metformin may do, then that's almost the ultimate in preventative medicine." The aim is to enroll 3,000 people between the ages of 65 and 79 for a six-year trial. But it's been slow going to get it funded. "The main obstacle with funding this study is that metformin is a generic drug, so no pharmaceutical company is standing to make money."

Researchers have turned to philanthropists and foundations, and has some pledges. The National Institute on Aging, part of the National Institutes of Health, set aside about $5 million for the research, but that's not enough to pay for the study which is estimated to cost between $45 and $70 million. The frustration over the lack of funding is that if the trial points to protective effects, millions of people could benefit. Currently the FDA doesn't recognize aging as a disease to treat, but the researchers hope this would usher in a paradigm shift - from treating each age-related medical condition separately, to treating these conditions together, by targeting aging itself.

This open access review paper covers the high points of what is presently known of the contribution of senescent cells to neurodegenerative conditions. Somatic cells become senescent throughout life, largely as they reach the Hayflick limit to replication, but also due to damage or a toxic local environment. Senescent cells halt replication and begin to secrete pro-inflammatory signals to attract the immune system. In youth, senescent cells are rapidly cleared by programmed cell death or by immune cells. With age, the immune system becomes less efficient. As a consequence senescent cells begin to accumulate, and they help to generate a state of chronic inflammation and tissue dysfunction, contributing to the onset and progression of age-related disease.

Cellular senescence is a ubiquitous process and is a state of irreversible cell cycle arrest, induced by a variety of cellular stimuli such as DNA damage, telomere shortening/dysfunction, oncogenic activation and chromatin disruption. Cellular senescence limits the replicative lifespan of cells and contributes to aging and age-related diseases. Senescent cells resist apoptosis and secrete persistent pro-inflammatory signals that are fatal to neighboring cells.

Neurodegenerative disease are characterized by chronic, progressive and pathological changes in the brain, such as neuronal death, abnormal aggregation of proteins and inflammation. Recent evidences suggest that the pathological changes in the neurodegenerative disease begins much ahead of the actual appearance of the symptoms. Prolonged exposure to stress such as DNA damage may induce cellular senescence and contribute to the pathogenesis of the disease by altering metabolism and affecting gene expression.

Alzheimer's disease accumulates toxic protein aggregates in the brain, including amyloid-beta plaques and tau tangles. Recent studies have shown that cellular senescence plays a role in developing and accumulating these toxic protein aggregates. As evidenced by increased SA-β-gal expression, p53 expression, a mediator of cellular senescence, an increase in the release of senescence-associated secretory phenotype (SASP) components, DNA damage, telomere attrition or damage, and senescence-like morphological changes, increased senescence is found in various cell types of Alzheimer's disease brains, including astrocytes, microglia, and neurons. In 2018 researchers found that cellular senescence is associated with tau protein aggregation in the brain. The researchers combined genomic analysis with pharmacological interventions to induce senescence in neurons, which led to increased tau aggregation and neuronal dysfunction. Conversely, clearance of senescent cells reduced tau-dependent pathology.

Parkinson's disease (PD) is the most common movement disorder and the second most prevalent neurodegenerative disease after Alzheimer's disease. Pre-symptomatic midbrain inflammation plays a crucial role in the pathology of PD. Cellular senescence triggers a pro-inflammatory response, the SASP, so senescence and SASP together are a strong contributing factor in the pathophysiology of PD. The dopaminergic (DA) neurons in PD has been noted to express various senescence markers. Neuronal senescence has also been recognized to contribute to the "inflammaging" seen in PD. In a recent study, it was found that α-synuclein (α-syn) aggregates triggers stress induced premature senescence in PD models. α-syn preformed fibrils triggers cellular senescence in astrocytes and microglia and leads to their activation. Overactivation of microglia has been detected in PD patients. Microglia when activated produce inflammatory products which might contribute to the dopaminergic neuronal death in PD patients.

Link: https://doi.org/10.3389/fragi.2023.1292053

There is a bidirectional relationship between declining kidney function and raised blood pressure, two prominent features of aging. The kidney is responsible for managing blood volume (one contribution to blood pressure) by adjusting the amount of water in blood as the bloodstream is filtered, a process that depends on some combination of the sensing of soluble factors and pressure. These complex systems fail with age in ways that can lead to raised blood pressure. Raised blood pressure in turn can damage the kidney directly, but also indirectly disrupt the balance of blood pressure control systems elsewhere in the body, such as via the constriction and dilation of blood vessels, or heart rate, that interact with those of the kidney via signaling molecules. It is a complex set of feedback loops, well-balanced in youth, but prone to damage that can cause a spiral into ever high blood pressure with advancing age.

Cardiovascular diseases affect kidney function. The aim of this study was to investigate the possible associations between hemodynamic parameters and change in kidney function in individuals aged 75 years and older. Data on hemodynamics and blood and urine samples were collected at baseline and during one-year visits. Hemodynamics were split into two groups based on median values. Changes in the estimated glomerular filtration rate (eGFR) were investigated between low and high groups for each hemodynamic parameter using analysis of variance. Changes in the albumin-creatinine ratio (ACR) were examined as binary outcomes (large increase vs. stable) using logistic regression.

The study population consisted of 252 participants. Participants in the high central systolic blood pressure (cSBP) group had a greater decline in eGFR than participants in the low cSBP group (-6.3% vs. -2.7%). Participants in the high aortic pulse wave velocity (aPWV) group, indicative of greater arterial stiffness, had a greater decline in eGFR than those in the low aPWV group (-6.8% vs. -2.5%). Other hemodynamic parameters were not associated with eGFR changes.

In conclusion, we found that elevated central aortic stiffness is associated with a greater decline in kidney function in old age. Since aPWV and cSBP both appear to be predictors of eGFR decline, it might be of interest to identify older individuals with elevated aortic stiffness. In this specific population, intensive blood pressure reduction might be justified in order to slow down the process of vascular aging and prevent kidney function decline.

Link: https://doi.org/10.3390/jcm13051334

It is well known that metabolic dysfunction and cardiovascular disease correlate well with an accelerated onset and progression of neurodegenerative conditions. This is particularly evident when considering these conditions in the context of obesity. Age-related diseases are the late stage consequences of a progressive accumulation of cell and tissue damage, and so a lifestyle that accelerates those underlying damage processes will produce a greater incidence of all of the common age-related diseases. Suffering from one form of age-related disease thus implies greater odds of suffering other forms of age-related disease, as they all descend from the same roots.

As demonstrated in today's open access paper, it isn't just the end result of outright dementia that correlates with the presence of other forms of age-relate disease. Suffering from metabolic or cardiovascular disease clearly correlates with the earlier stages of brain aging as well, such as cognitive decline, measures of brain volume, and the presence of small white matter hyperintensities that result from ruptured capillaries in brain tissue. Some of these harms derive from the underlying forms of damage that cause age-related disease, others are downstream of vascular aging or the inflammation of metabolic disease, others are a mix.

Cardiometabolic disease, cognitive decline, and brain structure in middle and older age

Cardiometabolic diseases (CMDs), a cluster of related conditions including type 2 diabetes (T2D), heart disease (HD), and stroke, are well-established individual risk factors for cognitive/brain aging and dementia. Cardiometabolic multimorbidity - the coexistence of ≥ 2 CMDs in the same individual - has risen greatly with population aging and is estimated to affect up to 30% of older adults. Recent studies have described a dose-dependent increase in dementia risk with one, two, and three co-morbid CMDs. However, less is known about the combined influence of CMDs on the subtle cognitive decline and brain structural changes that can occur in the decades before dementia diagnosis.

Brain magnetic resonance imaging (MRI) studies have linked cardiometabolic multimorbidity and unfavorable cardiovascular risk profiles to lower volumes of subcortical structures and poorer white matter microstructural integrity in older age. Moreover, recent studies suggest that cardiovascular and metabolic risk factors could be associated with vascular lesions already in middle age. However, evidence is lacking on the relationship between cardiometabolic multimorbidity and brain structure at different stages of life.

In the present study, using longitudinal data from adults that were middle-aged, younger than 60 years, as well as individuals older than 60 years in the UK Biobank, we aimed to (1) assess the association between cardiometabolic multimorbidity and changes in global and domain-specific cognitive function and (2) identify the brain regions that are possibly associated with cardiometabolic multimorbidity in middle and older age. 46,562 dementia-free UK Biobank participants completed a cognitive test battery at baseline and a follow-up visit 9 years later, at which point 39,306 also underwent brain magnetic resonance imaging. CMDs were ascertained from medical records.

A higher number of CMDs was associated with significantly steeper global cognitive decline in the older but not middle aged cohort. Additionally, the presence of multiple CMDs was related to smaller total brain volume, gray matter volume, white matter volume, hippocampal volume, and larger white matter hyperintensity volume, even in middle age. Thus CMDs are associated with cognitive decline in older age and worse brain structural health beginning already in middle age.

There has long been a school of thought on Alzheimer's disease that consideres it a form of diabetes, in which dysregulated glucose metabolism features prominently. This dysregulation certainly occurs; the study noted here isn't the only one to show that the aging brain no longer manages glucose adequately. The question is whether this mechanism is important relative to all of the other processes thought to contribute to the pathology of Alzheimer's disease and other neurodegenerative conditions, and where it fits in a chain of cause and consequence. Finding ways to demonstrate the relative importance of different mechanisms remains the primary challenge in developing a sufficient understanding of aging and age-related disease to make rapid progress towards effective therapies.

Defective brain glucose utilization is a hallmark of Alzheimer's disease (AD) while Type II diabetes and elevated blood glucose escalate the risk for AD in later life. Isolating contributions of normal aging from coincident metabolic or brain diseases could lead to refined approaches to manage specific health risks and optimize treatments targeted to susceptible older individuals.

We evaluated metabolic, neuroendocrine, and neurobiological differences between young adult (6 months) and aged (24 months) male rats. Compared to young adults, blood glucose was significantly greater in aged rats at the start of the dark phase of the day but not during the light phase. When challenged with physical restraint, a potent stressor, aged rats effected no change in blood glucose whereas blood glucose increased in young adults. Tissues were evaluated for markers of oxidative phosphorylation (OXPHOS), neuronal glucose transport, and synapses.

Outright differences in protein levels between age groups were not evident, but circadian blood glucose was inversely related to OXPHOS proteins in hippocampal synaptosomes, independent of age. The neuronal glucose transporter, GLUT3, was positively associated with circadian blood glucose in young adults whereas aged rats tended to show the opposite trend. Our data demonstrate aging increases daily fluctuations in blood glucose and, at the level of individual differences, negatively associates with proteins related to synaptic OXPHOS. Our findings imply that glucose dyshomeostasis may exacerbate metabolic aspects of synaptic dysfunction that contribute to risk for age-related brain disorders.

Link: https://doi.org/10.1016/j.nbas.2024.100116

Because epigenetic clocks are produced from DNA methylation data via machine learning approaches, correlating patterns of change with chronological age, it remains unclear as to what exactly they measure. Which processes of aging produce the specific DNA methylation changes used in any given clock? As yet that question has no answer. Thus a discovery process continues, in which researchers uncover clock behaviors such as a dependency on aspects of the circadian rhythm. Determining exactly which aspects will be one small part of a much longer process of understanding the details of the relationship between DNA methylation and the rest of cellular biochemistry. For now it is a caveat for those using aging clocks, epigenetic or otherwise - either pick a clock demonstrated to lack this behavior, or be consistent in time of day when measuring.

Since their introduction, epigenetic clocks have been extensively used in aging, human disease, and rejuvenation studies. In this article, we report an intriguing pattern: epigenetic age predictions display a 24-hour periodicity. We tested a circadian blood sample collection using 17 epigenetic clocks addressing different aspects of aging. Thirteen clocks exhibited significant oscillations with the youngest and oldest age estimates around midnight and noon, respectively. In addition, daily oscillations were consistent with the changes of epigenetic age across different times of day observed in an independant populational dataset.

While these oscillations can in part be attributed to variations in white blood cell type composition, cell count correction methods might not fully resolve the issue. Furthermore, some epigenetic clocks exhibited 24-hour periodicity even in the purified fraction of neutrophils pointing at plausible contributions of intracellular epigenomic oscillations. Evidence for circadian variation in epigenetic clocks emphasizes the importance of the time-of-day for obtaining accurate estimates of epigenetic age.

Link: https://doi.org/10.1111/acel.14170