Fight Aging! Newsletter, June 24th 2024

Fight Aging! Newsletter, June 24th 2024

Fight Aging! publishes news and commentary relevant to the goal of ending all age-related disease, to be achieved by bringing the mechanisms of aging under the control of modern medicine. This weekly newsletter is sent to thousands of interested subscribers. To subscribe or unsubscribe from the newsletter,
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The Makers of LY-D6/2 are Not Good Representatives of the Longevity Industry

There is a certain class of supplement manufacturer that follows the hype rather than the science: hype enables the ability to take cheap substances, obfuscate and market, and charge a sizeable premium. I think that the most offensive thing about the publicly available materials for the Leap Years supplement for dogs (referred to as LY-D6/2 here) is that they do not tell customers exactly what is in it. It is claimed to be some kind of vitamin B3 derivative to upregulate NAD+ and some kind of plant extract senolytic (likely fisetin or quercetin), both categories that have received a lot of attention in recent years.

On the one hand, pharmacological NAD+ upregulation is likely less effective than exercise. On the other hand, some senolytics are interesting, but many are only slightly senolytic. Of the well-known plant extracts, fisetin is interesting, but still lacking any published data in a species other than mice, while quercetin may be a component of the senolytic combination of dasatinib and quercetin, but is not meaningfully senolytic on its own. Given that Leap Years don’t tell us which they are using, or how large the dose is, there isn’t much that can be said about the prospects of the supplement strategy in advance. This is straightforwardly bad behavior on the part of this organization.

The only good thing I can find to say about this group is that they at least published the results of a study in dogs in the only significant benefit occurred in an owner-reported measure of cognitive function. There was no benefit to physical activity and frailty. One can draw no conclusions about any of this that are useful to the broader field because, again, we have no idea what is in this supplement.

A randomized, controlled clinical trial demonstrates improved owner-assessed cognitive function in senior dogs receiving a senolytic and NAD+ precursor combination

Age-related decline in mobility and cognition are associated with cellular senescence and NAD+ depletion in dogs and people. A combination of a novel NAD+ precursor and senolytic, LY-D6/2, was examined in this randomized controlled trial. Seventy dogs with mild to moderate cognitive impairment were enrolled and allocated into placebo, low dose, or full dose groups. Primary outcomes were change in cognitive impairment measured with the owner-reported Canine Cognitive Dysfunction Rating (CCDR) scale and change in activity measured with physical activity monitors.

This randomized controlled blinded trial is one of the first of its kind, evaluating an anti-aging supplement that targets two hallmarks of aging in senior dogs. This clinical trial used a pragmatic approach that included dogs with mild to moderate cognitive impairment who met age, weight and relatively broad health criteria. Dogs were followed to a primary endpoint at 3 months and a secondary endpoint at 6 months.

Fifty-nine dogs completed evaluations at the 3-month primary endpoint, and 51 reached the 6-month secondary endpoint. There was a significant difference in CCDR score across treatment groups from baseline to the primary endpoint with the largest decrease in the full dose group. No difference was detected between groups using in house cognitive testing. There were no significant differences between groups in changes in measured activity. The proportion of dogs that improved in frailty and owner-reported activity levels and happiness was higher in the full dose group than other groups, however this difference was not significant. Adverse events occurred equally across groups.

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Eliminating Germ Cells Removes the Sex Difference in Life Span from Killifish

There are a great many hypotheses as to why there is a difference in life expectancy between sexes in many species, and even more when it comes to humans. Since the difference exists in other species, it seems reasonable to throw out most of the thinking that involves behavioral differences or lifestyle choice differences in humans: arguments that men are more prone to risky behavior, less conscientious in use of medical resources, and so forth. From an evolutionary perspective, one can model how reproductive strategies might affect the process of natural selection and its interaction with pace of aging, but even if the models turn out to be correct – and they are usually much debated – that doesn’t say much about the specific biochemistry involved in determining life span differences between sexes.

Today’s open access research materials present a compelling argument for germline cells to orchestrate processes that lengthen female life span and shorten male life span. Removing the germline acts to shorten female life span and extend male life span in the short-lived killifish species. This dovetails nicely with the existing evolutionary perspectives, and at least narrows down the area of study for those who want to chase down specific mechanisms. The challenge in this arena is rarely in identifying a mechanism that may contribute to the end result of interest, it is to prove that this mechanism is important relative to all of the others that may or may not be involved. Fortunately, modern genetic technologies make it possible, albeit still expensive when conducted in volume, to knock out cell functions one by one. Researchers might progress from here to ever more specific acts of sabotage in germline cell biochemistry, in search of the mechanisms that affect life span.

The gender gap in life expectancy: are eggs and sperm partly responsible?

Women live longer than men. This isn’t unique to humans, either; we see this trend in a wide range of other animals. Biologists have theorized that the discrepancy in life expectancy between sexes might be partly related to reproduction, but how? Researchers have discovered for the first time that germ cells, the cells that develop into eggs in females and sperm in males, drive sex-dependent lifespan differences in vertebrate animals.

The researchers examined aging in the turquoise killifish, a small, fast-growing freshwater fish with a lifespan of only a few months. As in humans, female killifish live longer than males. However, when the researchers removed the germ cells from these fish, they found that males and females had similar lifespans. The team found that hormonal signaling was very different in females than in males. Female killifish without germ cells had significantly less estrogen signaling, which can shorten lifespan by increasing cardiovascular disease risk. The females also had significantly more growth factor signaling (insulin-like growth factor 1). This made the females grow larger while also suppressing signals within the body important for maintaining health and slowing aging. In contrast, male killifish without germ cells had improved muscle, skin, and bone health. Interestingly, these fish had increased amounts of a substance that activates vitamin D, as well as evidence of vitamin D signaling in their muscles and skin.

Sex-dependent regulation of vertebrate somatic growth and aging by germ cells

The function of germ cells in somatic growth and aging has been demonstrated in invertebrate models but remains unclear in vertebrates. We demonstrated sex-dependent somatic regulation by germ cells in the short-lived vertebrate model Nothobranchius furzeri. In females, germ cell removal shortened life span, decreased estrogen, and increased insulin-like growth factor 1 (IGF-1) signaling. In contrast, germ cell removal in males improved their health with increased vitamin D signaling. Body size increased but was caused by different signaling pathways in the two sexes, i.e., IGF-1 and vitamin D in females and males, respectively. Thus, vertebrate germ cells regulate somatic growth and aging through different pathways of the endocrine system, depending on the sex, which may underlie the sexual difference in reproductive strategies.

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Mid-Life Chronic Inflammation Contributes to Measures of Late Life Frailty

Chronic inflammation is a feature of aging. Constant unresolved inflammatory signaling arises from a number of distinct causes, but leads to significant disruption of cell and tissue function, and contributes to the onset and progression of age-related disease. The list causes includes a growing population of lingering senescent cells, all secreting pro-inflammatory signal molecules that can be useful in the short term, but become harmful when sustained over the long term. The list also includes some of the consequences of mitochondrial dysfunction, wherein fragments of mitochondrial DNA are found in the cytosol or outside cells, where they can provoke the innate immune system due to a similarity to bacterial DNA.

In today’s open access paper, researchers show a correlation between degree of chronic inflammation and later progression towards lack of physical capacity and frailty, as assessed by gait speed. The data captures a modest decline in physical function in people who are not earnestly sick. For context regarding the numbers given, the average gait speed for people in their 60s and 7ps is 124 cm/s, and thus high measures of inflammation markers in mid-life predicts an average ~8% decline of physical function over the next 20 years. Human epidemiological studies struggle to show correlation, but causation is largely well demonstrated in analogous animal studies. Chronic inflammation is an important problem in the biology of aging, and effective solutions are very much needed.

Associations of mid-to-late-life inflammation with late-life mobility and the influences of chronic comorbidities, race, and social determinants of health: The Atherosclerosis Risk in Communities Study

An estimated 15.4 million older Americans are unable to walk two to three city blocks. Poor physical function, such as slower walking speed, leads to poor quality of life, institutionalization, incident disability, high healthcare costs, and high mortality in community-dwelling older adults and is considered the “sixth vital sign” for older patients. The underlying mechanisms contributing to slowing gait speed and dismobility are poorly understood. One potential pathway is direct inflammatory effects on muscle and other tissues, leading to wasting and weakness, triggering pathways that contribute to muscle breakdown, fatty infiltration, and fibrosis which can lead to muscle weakness, inefficiency, and mobility disability.

High levels of interleukin-6, high sensitivity C-reactive protein (hsCRP), tumor necrosis factor alpha (TNFα), and TNFα soluble receptors are associated with slow walking speed and frailty primarily in older adults, supporting a role for inflammation on age-related mobility declines during late-life. However, whether chronically elevated levels of inflammation prior to older age, when interventions could be more effective, are associated with late-life mobility has not been well studied. Most studies only examined inflammation measured during older ages and did not consider duration of exposure from midlife, which would provide stronger evidence for causal mechanisms. Furthermore, relating inflammatory markers measured across the mid-to-late-life transition on late-life mobility could identify earlier intervention opportunities, yet studies of inflammation during this critical period are limited, particularly in diverse populations.

Among 4,758 community-dwelling participants in the Atherosclerosis Risk in Communities Study (ARIC), high-sensitivity C-reactive protein (hsCRP) was measured over 20+ years: in midlife at study visit 2 (V2: 1990-1992, 47-68 years); at visit 4 (1996-1998, 53-74 years); and with concurrent late-life 4-meter gait speed at visit 5 (2011-2013, 67-88 years, mean 75 years). We examined associations of late-life gait speed with midlife hsCRP (visit 2 continuous and clinically high ≥3 mg/L), with 20-year hsCRP history from midlife (visit 2 to visit 5 average continuous hsCRP and clinically high ≥3 mg/L) and with inflammation accumulation (visits and years with high hsCRP).

High midlife hsCRP was associated with slower late-life gait speed, even among those without chronic conditions in midlife: -4.6 cm/s. Importantly, sustained high hsCRP was associated with a 20-year slowing of -10.0 cm/s among those who never experienced obesity, diabetes, or hypertension over the 20-year period. Inflammation in midlife may contribute to clinically meaningful late-life slowing of gait speed, even among otherwise healthy-appearing adults. Regular monitoring and interventions for inflammation may be warranted from midlife.

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Cells Can Eject Damaged Mitochondria

A sizable fraction of cell signaling is carried in extracellular vesicles, membrane-wrapped packages of molecules. In the course of investigating cell signaling, researchers have noted that some fraction of these vesicles are in fact mitochondria. Cells can readily ingest mitochondria, just as they do other vesicles, and put the mitochondria to work. Mitochondria are organelles descended from ancient symbiotic bacteria, primarily responsible for generating chemical energy store molecules to power cell processes, but also deeply integrated into a wide range of cellular mechanisms beyond this. Mitochondria have their own DNA, replicate like bacteria, and are cleared when damaged by the quality control mechanisms of mitophagy, a form of autophagy that delivers mitochondria to a lysosome where they are broken down. With aging, mitochondria become dysfunctional, and this dysfunction is thought to be important in aging.

The popular science article noted here reports on the discovery that cells in aged tissues can eject damaged mitochondria instead of recycling them. In this case the mitochondria are encapsulated into a vesicle rather than released as-is. The interesting question is what this might do to surrounding cells if they fail to direct these mitochondria to their lysosomes. To what degree can a dysfunctional cell cause harm by shipping out damaged mitochondria for other cells to ingest and react to? One thought is that while the general malaise in mitochondrial function in tissues throughout the body appears to stem from widespread changes in the expression of important nuclear genes, rare cases of severe damage to mitochondrial DNA can produce mitochondria that are both dysfunctional and capable of replicating more effectively than their functional peers, taking over the cell. Can that problem be exported from a dysfunctional cell to a functional cell, and how often does that occur?

The most interesting of strategies to address mitochondrial dysfunction with aging are (a) partial reprogramming, attempting to recreate the processes of early embryonic development that reset mitochondrial function, and (b) transplantation of large numbers of functional mitochondria harvested from cell cultures. The latter is more likely to become a viable, readily available therapy in the near future, as many clinics already work with harvested extracellular vesicles. In principle it should little matter whether and to what degree cells spread mitochondrial dysfunction given a cost-effective treatment that supplies new mitochondria to a sizable fraction of cells in a tissue.

Taking Out the Trash: An Alternative Cellular Disposal Pathway

Organelle health is vital to a cell’s function. Consequently, cells have many mechanisms to repair or eliminate defective organelles. In a recent paper, researchers determined that cardiac myocytes and other cells use secretion to remove mitochondria from the cell when lysosomal degradation is inhibited. Mitochondria generate most of the cell’s energy. However, when they become dysfunctional, damaged, or old, mitochondria can turn into pro-death organelles, which produce reactive oxygen species that damage the cell’s proteins and DNA. This is a major problem for cardiac myocytes, which rely on the energy produced by mitochondria to contract. Additionally, the body cannot replace these particular cells because they do not divide.

Cells have various quality control mechanisms to detect and repair dysfunctional mitochondria, but when the organelles are too damaged, the cell degrades them using lysosomes. We wanted to determine what happens to the cell when the lysosomes are not functioning well or are overwhelmed, and if there was another pathway to temporarily deal with the damaged mitochondria. This information is of particular importance to patients with Danon’s disease, who have mutations in a lysosomal protein that causes cardiomyopathy.

We discovered that fibroblasts and cardiac myocytes secrete mitochondria inside extracellular vesicles (EV) when their lysosomal function is compromised or overwhelmed. This encapsulation ensures that the mitochondria do not elicit a dangerous immune response once outside the cell because of their bacterial origin. The mitochondria-containing EV originate from within multivesicular bodies (MVB), which either deliver the cargo to the lysosomes for degradation or ship everything to the plasma membrane for secretion. We found that Rab7, a protein present on the MVB’s outer membrane, is a regulator involved in dictating the fate of the vesicles. We believe that active Rab7 directs the EV toward the lysosomes, but in the absence of this protein or when it is inactive, the cell will traffic the EV to the plasma membrane.

Once cardiac myocytes release the mitochondria-containing EV, resident cardiac macrophages and other cells in the heart internalize the vesicles to degrade them through their lysosomes. The EV do not seem to enter circulation but stay within the heart. Ultimately, this is an alternative garbage disposal pathway used by cells to get rid of dysfunctional and damaged mitochondria when they cannot degrade the organelles in their own lysosomes.

Mitochondria are secreted in extracellular vesicles when lysosomal function is impaired

Mitochondrial quality control is critical for cardiac homeostasis as these organelles are responsible for generating most of the energy needed to sustain contraction. Dysfunctional mitochondria are normally degraded via intracellular degradation pathways that converge on the lysosome. Here, we identified an alternative mechanism to eliminate mitochondria when lysosomal function is compromised. We show that lysosomal inhibition leads to increased secretion of mitochondria in large extracellular vesicles (EVs). The EVs are produced in multivesicular bodies, and their release is independent of autophagy. Deletion of the small GTPase Rab7 in cells or adult mouse heart leads to increased secretion of EVs containing ubiquitinated cargos, including intact mitochondria. The secreted EVs are captured by macrophages without activating inflammation. Hearts from aged mice or Danon disease patients have increased levels of secreted EVs containing mitochondria indicating activation of vesicular release during cardiac pathophysiology. Overall, these findings establish that mitochondria are eliminated in large EVs through the endosomal pathway when lysosomal degradation is inhibited.

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Reviewing What is Known of the Aging of the Gut Microbiome

Evidence obtained from animal and human studies in recent years suggests that the composition of the gut microbiome influences long-term health to a similar degree as choices relating to exercise and dietary choices. Certainly, the balance of populations making up the gut microbiome changes with age. Pro-inflammatory microbes grow in number at the expense of microbial populations responsible for the generation of beneficial metabolites, such as butyrate, which is known to upregulate neurogenesis. This process of gut microbiome aging begins quite early in adult life, perhaps as early as the 30s. These shifts may or may not be connected to shifts in the immune system and its ability to clear problematic microbes.

Fortunately several approaches to therapy have been demonstrated to produce a lasting rejuvenation of the gut microbiome, at least in animal models. Arguably the best of these is fecal microbiota transplantation using stool samples from a young donor. In animal studies, this approach as been shown to produce a lasting change in the balance of populations of the gut microbiome, improve health, and extend life span. This approach is used as a therapy in the treatment of C. difficile infection, but is not otherwise well developed. For those intent on trying this for themselves, it is possible to purchase screened stool samples from groups like Human Microbes. That screening for potentially problematic microbes in the donor sample is increasingly important as recipient age increases, as older people can be vulnerable to microbes that a younger person can tolerate.

The human gut microbiome and aging

The gastrointestinal microbiome is the collection of bacterial cells that reside within the human gastrointestinal tract representing more cells that are contained within the human body, and a metagenome (combined genome of these commensal organisms) that is far larger than the human genome. This community of organisms has been observed to change over the lifespan. Machine-learning-based analysis of published gut microbiome datasets could predict a subject’s chronologic age within 5.9 years, although this study was conducted largely independent of any health information. A cross-sectional study across the lifespan (age 1 to over 100) in a Japanese population showed a characteristic microbiome within infants and young children prior to weaning, then a transition to a more diverse microbiome associated with introduction of solid foods. This diverse and dynamic microbiome develops until early adulthood and then becomes relatively stable when it begins to show a decline in diversity after peaking late in life (around 65) and becoming more pronounced in individuals older than 80 years.

Researchers have observed microbiome signatures that became more unique to the individual at extremes of age which may reflect the microbiome becoming tailored to the individual’s diet and living environment that perhaps varies less at extremes of age. Intriguingly, very long-lived individuals (over 100 years old) have shown a distinct gut microbiome profile with greater diversity a high abundance of health-associated taxa such as Christensenellaceae and Akkermansia. Although the gut microbiome changes across the lifespan, there are features that have been associated with diseases that develop at different phases of life and contribute to the development of age-related disease later in life. Of particular interest are the microbiomes of “super-agers” who reach extremes of age in relatively good health and have the potential to offer insights into how the microbiome can affect longevity and resistance to age-related diseases.

Although age itself likely contributes to changes in the gastrointestinal microbiome, it is also greatly impacted by the environment in which an individual lives and ages. An exploration of data from metagenomic sequencing of microbiome samples across Europe, Africa, North and South America showed that there were distinct features of each geographic area throughout the lifespan. Much of the literature notes changes in taxa with age that tends to be conserved across different areas of the world. There are, however, notable differences depending on the region in which the study was undertaken. Studies of cohorts in Italy and Ireland have shown decreased abundances of Roseburia with aging, while studies cohorts in Korea and China have reported increases in this genus. Bacteroidetes are generally described as increasing with age, but the converse was observed among healthy older Indonesians. A study of healthy centenarians from India and comparing them with studies previously mentioned from Italy, China, and Japan found unique features in the Indian population such as lower Bacteroidetes, higher Enterobacteriaceae among the Indian cohort. Akkermansia, usually associated with healthy aging, was associated with frailty in a cohort of Chinese older adults.

These discrepancies highlight the extremely complex relationship between the gut microbiome and aging, which is affected not only by the myriad interactions between the host-specific organisms in the microbiome, but also the diet and environment in which the individual ages.

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A Return to Quasi-Programmed and Hyperfunction Views of Aging

Is aging actively selected for by evolutionary processes, a program that provides some advantage to a species, or is aging the polar opposite, the consequence of a lack of selection pressure on late life health? The latter is the present mainstream view of aging, that aging arises because early reproduction is favored by evolution, and thus systems evolve that are initially effective but decline over time. Aging is a side-effect of these maladapted systems, a process called antagonistic pleiotropy.

The ideas put forward by the smaller part of the research community that sees aging as an evolved program are themselves evolving quite rapidly. It is interesting to dip a toe into that water every so often to see where matters stand. At present there is a fair amount of interest in ideas that fall under the heading of quasi-programmed aging, which do not clearly belong to either the traditional programmed aging viewpoints or the antagonistic pleiotropy viewpoints. The hyperfunction view of aging is one of these ideas, in which, to oversimplify, aging is seen as the consequence of developmental programs that continue to run past their useful span of time.

While ruling out programmed aging, evolutionary theory predicts a quasi-program for aging, a continuation of the developmental program that is not turned off, is constantly on, becoming hyper-functional and damaging, causing diseases of aging. Could it be switched off pharmacologically? This would require identification of a molecular target involved in cell senescence, organism aging and diseases of aging. Notably, cell senescence is associated with activation of the TOR (target of rapamycin) nutrient-sensing and mitogen-sensing pathway, which promotes cell growth, even though the cell cycle is blocked.

Is TOR involved in organism aging? In fact, in yeast (where the cell is the organism), caloric restriction, rapamycin, and mutations that inhibit TOR all slow down aging. In animals from worms to mammals caloric restrictions, life-extending agents, and numerous mutations that increase longevity all converge on the TOR pathway. And, in humans, cell hypertrophy, hyper-function and hyperplasia, typically associated with activation of TOR, contribute to diseases of aging. Theoretical and clinical considerations suggest that rapamycin may be effective against atherosclerosis, hypertension and hyper-coagulation (thus, preventing myocardial infarction and stroke), osteoporosis, cancer, autoimmune diseases and arthritis, obesity, diabetes, macular degeneration, Alzheimer’s and Parkinson’s diseases.

Finally, I discuss that extended life span will reveal new causes for aging (e.g. reactive oxygen species, ‘wear and tear’, Hayflick limit, stem cell exhaustion) that play a limited role now, when quasi-programmed senescence kills us first.

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Age-Slowing Interventions Produce Diminished Effects with Increased Species Life Span

Calorie restriction has a sizable effect on health and life span in the short-lived species used in scientific studies of aging, and produces sweeping changes in the regulation of cellular biochemistry. The combination of these two points has ensured that near all approaches discovered to slow aging to date operate on aspects of cellular biochemistry that are involved in the calorie restriction response. In the course of producing a body of data in numerous species including worms, flies, and mice, it has become clear that short-lived species are much more responsive to these interventions than is the case for long-lived species. There is an argument to be made that most of the research and development in the field of aging is looking in the wrong places for approaches that will work well in long-lived mammals such as our own species. That doesn’t mean that the field as a whole is incapable of producing sizable gains in life span, however. It would be premature to draw that conclusion.

Well-documented anti-aging treatments across species of increasing complexity include drugs such as rapamycin, resveratrol, spermidine, chloroquine, and even medications historically employed for treating different diseases, like metformin, which is used in the management of type 2 diabetes. The decreasing magnitude of the positive effect with increasing species complexity in anti-aging treatments is obvious. Thus, we noted the positive effects of metformin decreased from 50% in S. cerevisiae to negligible (if any) effects in humans. Similarly, the effects of resveratrol decreased almost linearly from 70% in S. cerevisiae to 41% in Drosophila, to 30% in C. elegans, to 26% in rodents. The impact of rapamycin on lifespan across species decreased progressively, from 57% in S. cerevisiae to approximately 29% in Drosophila, further declining to 25% in C. elegans, and ultimately reaching 13% in rodents.

The limited translatability between species of increasing complexity can be explained by a number of factors. The effectiveness or significance of the targeted molecule from a pathway might differ in various metabolic scenarios. For example, the anti-aging mechanisms of resveratrol primarily involve ameliorating oxidative stress by scavenging reactive oxygen species (ROS). However, ROS play a more significant role in flying species like Drosophila than in mammals, which may possess additional mechanisms to counteract ROS. Indeed, recent research has revealed a more complex and beneficial role of ROS in regulating metabolism, development, and lifespan.

Second, the weight of targeted signaling pathways differs for a species’ general metabolism. Therefore, single mutations that reduce insulin/IGF-1 signaling can significantly increase the lifespan of simple organisms such as C. elegans and D. melanogaster. However, the increased complexity of the pathway, attributed to additional regulators like insulin and growth hormone, has made it challenging to distinguish the roles of each key component in mammalian longevity.

Third, redundancy in pathways is a widespread phenomenon in species of increasing complexity, observed across all forms of life. It has developed as a safeguard against disturbances that might otherwise interfere with essential processes, such as mutations or shifts in the environment. Thus, blocking one pathway does not necessarily impede the cellular or organismal process.

Fourth, as we make progress into research on anti-aging therapies, the challenges posed by the increasing complexity of species remind us that, much like many aspects of biology and medicine, there exists a law of diminishing returns. While the initial interventions may yield significant and noticeable impacts, the subsequent benefits might be less pronounced with the addition of more layers of complexity and control.

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Lower Ceremide Levels in Aged GHRH Knockout Mice

GHRH knockout mice are one of the longest-lived lineages. It remains the case that disrupted growth hormone signaling extends life to a greater degree than any of the other interventions tested in mice. The equivalent Laron syndrome population in humans clearly doesn’t experience the same sizable extension of life span, however. This should perhaps tell us that researchers must look elsewhere for approaches to the treatment of aging in long-lived mammals. The most well studied approaches to extend healthy life span in mice, meaning calorie restriction and disruption of growth hormone signaling, do not improve human life span to anywhere near the same degree.

Dysregulation of growth hormone (GH) signaling consistently leads to increased lifespan in laboratory rodents, yet the precise mechanisms driving this extension remain unclear. Understanding the molecular underpinnings of the beneficial effects associated with GH deficiency could unveil novel therapeutic targets for promoting healthy aging and longevity. In our pursuit of identifying metabolites implicated in aging, we conducted an unbiased lipidomic analysis of serum samples from growth hormone-releasing hormone knockout (GHRH-KO) female mice and their littermate controls.

Employing a targeted lipidomic approach, we specifically investigated ceramide levels in GHRH-KO mice, a well-established model of enhanced longevity. While younger GHRH-KO mice did not exhibit notable differences in serum lipids, older counterparts demonstrated significant reductions in over one-third of the evaluated lipids. In employing the same analysis in liver tissue, GHRH-KO mice showed pronounced downregulation of numerous ceramides and hexosylceramides, which have been shown to elicit many of the tissue defects that accompany aging (e.g., insulin resistance, oxidative stress, and cell death). Additionally, gene expression analysis in the liver tissue of adult GHRH-KO mice identified substantial decreases in several ceramide synthesis genes, indicating that these alterations are, at least in part, attributed to GHRH-KO-induced transcriptional changes.

These findings provide the first evidence of disrupted ceramide metabolism in a long-lived mammal. This study sheds light on the intricate connections between GH deficiency, ceramide levels, and the molecular mechanisms that influence lifespan extension.

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Assessing the Effects of Intermittent Fasting and Calorie Restriction on the Gut Microbiome

Evidence suggests that the composition of the gut microbiome is as influential on long-term health as choices in diet and exercise. The relative proportions of microbial species shift with age, favoring harmful pro-inflammatory microbes over those that produce beneficial metabolites. It is reasonable to ask how much of the beneficial effects of fasting and calorie restriction are mediated via the gut microbiome, via slowing or reducing age-related changes in these microbial populations. With that in mind, researchers are beginning to assess how fasting and calorie restriction alter the behavior and balance of microbial populations making up the gut microbiome. The paper here is one example of this sort of study.

As a principal modulator of the gut microbiome (GM) and weight status, nutritional input holds great therapeutic promise for addressing a wide range of metabolic dysregulation. The GM must regulate its growth rate and diversity in response to nutrient availability and population density. Such maintenance is affected by caloric restriction (CR) coupled with periods of feeding and intermittent fasting (IF). The current study incorporates protein pacing (P), defined as four meals/day consumed evenly spaced every 4 hours, consisting of 25-50 g of protein/meal. Indeed, we have previously characterized a dietary approach of calorie-restricted IF-P combined and P alone.

In this current work, we compare the effects of two low-calorie dietary interventions matched for weekly energy intake and expenditure; continuous caloric restriction on a heart-healthy diet (CR) aligned with current United States (US) dietary recommendations versus our calorie-restricted IF-P diet. The current randomized controlled study describes distinct fecal microbial and plasma metabolomic signatures between combined IF-P (n = 21) versus a heart-healthy, calorie-restricted (CR, n = 20) diet matched for overall energy intake in free-living human participants (women = 27; men = 14) with overweight/obesity for 8 weeks.

Gut symptomatology improves and abundance of Christensenellaceae microbes and circulating cytokines and amino acid metabolites favoring fat oxidation increase with IF-P, whereas metabolites associated with a longevity-related metabolic pathway increase with CR. The plasma metabolome analysis revealed the existence of distinct metabolite signatures in IF-P and CR groups, with the convergence of multiple metabolic pathways. Differences indicate GM and metabolomic factors play a role in weight loss maintenance and body composition. This data may inform future GM-focused precision nutrition recommendations using larger sample sizes of longer duration.

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Reviewing the Link Between Peripheral Vascular Aging and the Brain

The development of cardiovascular disease outside the brain is thought to contribute to the aging of the brain. The brain is an energy-hungry tissue, and any reduction in blood flow, such as through atherosclerotic narrowing of the arteries and heart failure, will cause harm and functional decline over time. At the same time, and while every organ influences every other organ in some way, it is also the case that vascular aging and brain aging arise to some degree independently due to same underlying processes of aging that operate in every tissue. Mitochondrial dysfunction occurs in the brain just as much as it does in the vasculature, for example, and for reasons centered on the cell, not on the tissue – such as epigenetic changes that occur due to nuclear DNA double strand break repair, or stochastic mutation of mitochondrial DNA.

Aging is the greatest non-modifiable risk factor for most diseases, including cardiovascular diseases (CVD), which remain the leading cause of mortality worldwide. Robust evidence indicates that CVD are a strong determinant for reduced brain health and all-cause dementia with advancing age. CVD are also closely linked with peripheral and cerebral vascular dysfunction, common contributors to the development and progression of all types of dementia, that are largely driven by excessive levels of oxidative stress, e.g., reactive oxygen species (ROS). Emerging evidence suggests that several fundamental aging mechanisms (e.g., “hallmarks” of aging), including chronic low-grade inflammation, mitochondrial dysfunction, cellular senescence, and deregulated nutrient sensing contribute to excessive ROS production and are common to both peripheral and cerebral vascular dysfunction.

Therefore, targeting these mechanisms to reduce ROS-related oxidative stress and improve peripheral and/or cerebral vascular function may be a promising strategy to reduce dementia risk with aging. Investigating how certain lifestyle strategies (e.g., aerobic exercise and diet modulation) and/or select pharmacological agents (natural and synthetic) intersect with aging “hallmarks” to promote peripheral and/or cerebral vascular health represent a viable option for reducing dementia risk with aging. Therefore, the primary purpose of this review is to explore mechanistic links among peripheral vascular dysfunction, cerebral vascular dysfunction, and reduced brain health with aging. Such insight and assessments of non-invasive measures of peripheral and cerebral vascular health with aging might provide a new approach for assessing dementia risk in older adults.

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BMP-7 Promotes Heart Regeneration

BMP-7 is a myokine, involved in muscle growth and upregulated in response to exercise. It is also involved in the development of muscle tissue in early life. One of the reasons that researchers are interested in this gene and related mechanisms of muscle maintenance, growth, and regeneration is to be able to promote greater recovery in an injured heart. Heart muscle is one of the least regenerative tissues in the body, and this limits recovery from a heart attack and resilience to the harmful aged tissue environment. Activating pathways involved in development or exercise may be the road to therapies that can incrementally improve the present situation for older people with heart disease.

Zebrafish have a lifelong cardiac regenerative ability after damage, whereas mammals lose this capacity during early postnatal development. This study investigated whether the declining expression of growth factors during postnatal mammalian development contributes to the decrease of cardiomyocyte regenerative potential. Besides confirming the proliferative ability of neuregulin 1 (NRG1), interleukin (IL)1b, receptor activator of nuclear factor kappa-Β ligand (RANKL), insulin growth factor (IGF) 2, and IL6, we identified other potential pro-regenerative factors, with BMP7 exhibiting the most pronounced efficacy.

Bmp7 knockdown in neonatal mouse cardiomyocytes and loss-of-function in adult zebrafish during cardiac regeneration reduced cardiomyocyte proliferation, indicating that Bmp7 is crucial in the regenerative stages of mouse and zebrafish hearts. Conversely, bmp7 overexpression in regenerating zebrafish or administration at post-mitotic juvenile and adult mouse stages, in vitro and in vivo following myocardial infarction, enhanced cardiomyocyte cycling. Mechanistically, BMP7 stimulated proliferation through BMPR1A/ACVR1 and ACVR2A/BMPR2 receptors and downstream SMAD5, ERK, and AKT signaling. Overall, BMP7 administration is a promising strategy for heart regeneration.

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A Decellularized Liver Patch Improves Function in Rats

Decellularization involves stripping cells from donor tissue to leave behind the extracellular matrix and its chemical cues. That extracellular matrix can then be repopulated with patient-matched cells and transplanted, in principle minimizing many of the issues associated with tissue transplantation. The initial hype over decellularization has somewhat faded, but many groups continue to work with decellularized tissue in parallel with other approaches to tissue engineering. The production of thin patches of functional tissue to apply to organs such as the liver or heart has shown some promise in recent years, and here researchers demonstrate the ability to improve the function of damaged livers in rats via this strategy.

Liver fibrosis is primarily induced by liver inflammation, which triggers continuous secretion of the extracellular matrix (ECM) by hepatic stellate cells (HSCs). This secretion promotes liver repair, but eventually leads to fibrosis. The treatment of liver fibrosis is a complex process, and the optimal therapeutic strategy is to reverse the fibrotic progression. Conventional cell therapy has demonstrated promise in addressing fibrosis/cirrhosis. However, the direct infusion of hepatocytes faces challenges due to limited hepatocyte sources, poor cell viability, and the requirement for a large number of transplanted parenchymal functional hepatocytes.

Instead of stem cell therapy, liver tissue engineering presents another alternative therapeutic strategy. Tissue-engineering approaches for bioengineering of functional hepatic constructs shows potential to replicate liver physiological structures. However, to restore the normal hepatic architecture and functions, tissue engineering strategies for liver regeneration should position bioengineered hepatic constructs into the defect site of an injured liver instead of heterotopic implantation (subcutaneous or intraperitoneal accesses). Thus, cell sheet engineering technology holds promise because the transplanted cells might be better retained due to preserved contacts between the cells and the ECM.

We developed a hepatic patch by combining decellularized liver matrix (DLM) with the hepatocyte growth factor (HGF)/heparin-complex and evaluated its restorative efficacy. In vitro prophylactic results, the HGF/heparin-DLM patches effectively mitigated CCl4-induced hepatocyte toxicity and restored the cytotoxicity levels to the baseline levels by day 5. Furthermore, these patches restored albumin synthesis of injured hepatocytes to more than 70% of the normal levels within 5 days. In vivo, HGF/heparin-DLM patches attached to the liver and gut exhibited a significant decrease in collagen content (4.44 times and 2.77 times, respectively) and an increase in glycogen content (1.19 times and 1.12 times, respectively) compared to the fibrosis group after 1 week, separately. Thus the newly designed hepatic patch holds promise for regeneration therapy and preventive health care for liver tissue engineering.

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Lower Dose Senolytics Fail to Prevent Cognitive Decline in Female Rats

Researchers here evaluate the effects of a longer term dosing schedule of a few different senolytic drugs in rats, 5 days on and 14 days off repeated for 7 months. The dose of dasatinib and quercetin used is about half of that shown to be effective in clearance of senescent cells in mice and people, but those higher doses have typically not been used as frequently or for as long. That this fails to affect cognitive decline in female rats is a data point, to contrast with other studies in which senolytic therapies have slowed cognitive decline or produced benefits in animal models of neurodegenerative conditions. Determining dosage is a hard problem generally, and this is still a work in progress for first generation senolytic therapies such as the combination of dasatinib and quercetin. Near all such effort in the field is directed towards new senolytics under development by biotech companies.

There are sex differences in vulnerability and resilience to the stressors of aging and subsequent age-related cognitive decline. Cellular senescence occurs as a response to damaging or stress-inducing stimuli. The response includes a state of irreversible growth arrest, the development of a senescence-associated secretory phenotype, and the release of pro-inflammatory cytokines associated with aging and age-related diseases. Senolytics are compounds designed to eliminate senescent cells. Our recent work indicates that senolytic treatment can preserve cognitive function in aging male F344 rats. The current study examined the effect of senolytic treatment on cognitive function in aging female rats.

Female F344 rats (12 months) were treated with dasatinib (1.2 mg/kg) + quercetin (12 mg/kg) or ABT-263 (12 mg/kg) or vehicle for 7 months. Examination of the estrus cycle indicated that females had undergone estropause during treatment. Senolytic treatment may have increased the differences between sexes in behavioral stress responsivity, particularly for the initial training on the cued version of the water maze. However, pre-training on the cue task reduced stress responsivity for subsequent spatial training and all groups learned the spatial discrimination. In contrast to preserved memory observed in senolytic-treated males, all older females exhibited impaired episodic memory relative to young (6-month) females. We suggest that the senolytic treatment may not have been able to compensate for the loss of estradiol, which can act on aging mechanisms for anxiety and memory independent of cellular senescence.

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Is 70 the New 60?

The interesting data in this open access preprint paper is a concrete example of the prevailing trend in human life expectancy. A slow, steady increase in life expectancy (both at birth and remaining life expectancy at middle age) has been underway for decades, driven in part by improvements in approaches to treating age-related disease. To a first approximation, these population-wide effects on the underlying processes of aging achieved over past decades have been unintentional side-effects of progress in medical science. Deliberate targeting of the mechanisms of aging is still a comparatively new idea, and too few people are making use of approaches that may have some benefit to noticeably affect the epidemiology of the entire population.

The World Health Organization (WHO) has proposed a framework in which healthy ageing is considered not from the perspective of disease but based on an individual’s ability to be and do the things they value. This ability is understood to be determined by individual-level attributes – a person’s “intrinsic capacity”, as well as the environments they inhabit and the interaction between the individual and these environments. Since intrinsic capacity is framed as a continuum that can be considered across the second half of life, it can potentially be used to compare incremental changes among both relatively robust and severely disabled individuals.

We have previously examined intrinsic capacity in two large longitudinal studies of the English and Chinese populations: the English Longitudinal Study on Ageing (ELSA) and the China Health and Retirement Longitudinal Study (CHARLS) Both analyses identified an intrinsic capacity construct that comprises subdomains of cognitive, locomotor, sensory and psychological capacity and a further subdomain labelled vitality, which may represent underlying age-related biological changes and energy balance. The aim of this paper is to conduct a longitudinal analysis of cohort trends in intrinsic capacity in these same studies to determine whether older adults in England and China are experiencing the same, better or worse capacity than people of similar ages in the past.

Our research suggests there have been significant improvements in functioning in more recent cohorts of older people in both England and China. Within ELSA, more recent cohorts entered older ages with higher levels of intrinsic capacity, and subsequent declines were less steep than for earlier cohorts. Improvements were seen in all subdomains. The observed improvements are substantial. To avoid undue extrapolation, we limited our assessment to direct comparisons of capacity in participants of different cohorts at the same age. Currently, the overlap between adjacent cohorts in the ELSA study is 6 years, and participants of non-adjacent cohorts cannot be directly compared. However, even with these limitations, we still found that a 68-year-old ELSA participant born in 1950 had higher intrinsic capacity than a 62-year-old born just 10 years earlier.

Improvement in cognition was even more substantial. When comparing earlier cohorts, additional improvements are observed, although the gains between these cohorts are not quite as large as between the 1940 and 1950 cohorts. Thus, while our models suggest that today’s 70-year-olds have the equivalent functioning to substantially younger adults in previous generations (perhaps 70 really is the new 60), our direct assessments can only confirm that 68 is the new 62.

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A Short Review of Effects of Lifestyle Choice on Epigenetic Age

As researchers here note, there is ample evidence to suggest that lifestyle choices known to correlate with modestly longer life expectancy in epidemiological studies also correlate with lower measures of biological age. These include epigenetic clocks and combinations of physiological measures such as phenotypic age. None of this is terribly surprising. When it is clear that exercise improves traditional measures of health and life expectancy, only a poor measure of biological age would not also be improved.

Biological age is a concept that uses bio-physiological parameters to account for individual heterogeneity in the biological processes driving aging and aims to enhance the prediction of age-related clinical conditions compared to chronological age. Although engaging in healthy lifestyle behaviors has been linked to a lower mortality risk and a reduced incidence of chronic diseases, it remains unclear to what extent these health benefits result from slowing the pace of the biological aging process. This short review summarized how modifiable lifestyle factors – including diet, physical activity, smoking, alcohol consumption, and the aggregate of multiple healthy behaviors – were associated with established estimates of biological age based on clinical or cellular/molecular markers, including Klemera-Doubal Method biological age, homeostatic dysregulation, phenotypic age, DNA methylation age, and telomere length.

Individuals who engage in a healthy lifestyle may exhibit a slower pace of biological aging, as their DNA methylation profile and physiological biomarkers are in a healthier state that typically indicates lower risks of mortality and age-related diseases. However, most studies linking lifestyle factors and biological aging are cross-sectional designs, making it difficult to establish causation. Furthermore, it is worth noting that previous research investigating lifestyle factors and biological aging was commonly obtained from specific US cohorts, such as NHANES and the Sister study, probably due to the difficulty of having both biological age measures and comprehensive lifestyle data in other large cohorts. More evidence derived from diverse populations needs to be included.

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