Fight Aging!

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Contents

• Modest Life Extension in Mice via CD38 Inhibition
• Aging of the Intestinal Barrier as a Driving Cause of Chronic Inflammation
• The Effective Altruism Community on the Merits of Philanthropy to Advance Cryonics for Brain Preservation
• Towards Enhanced Mitochondrial Fission to Improve Mitochondrial Function in Later Life
• A Taxonomy of Degree of Effort in Undertaking Interventions to Slow or Reverse Aging
• On Killing Senescent Cells with Natural Killer Cells
• An Example of a Very Targeted, Narrow Improvement of Immune Function in Aged Individuals
• Mitophagy Protein BNIP3 is Protective Against Inflammation and Muscle Aging
• Inflammatory Changes in Bone Marrow as a Precursor to Atherosclerosis
• Lifelong Exercise Preserves Muscle Stem Cells
• Considering Stem Cells in the Context of Cancer and Aging
• The Senescence-Associated Cell Transition and Interaction (SACTAI) Model of Tissue Aging
• In Replicative Senescence, Cells Become Senescent Slowly as Telomeres Shorten
• A Review of Some of What is Known of Aging in Liver Tissue
• Senolytics as a Treatment for Intervertebral Disc Degeneration

Modest Life Extension in Mice via CD38 Inhibition
https://www.fightaging.org/archives/2022/03/modest-life-extension-in-mice-via-cd38-inhibition/

Nicotinamide adenine dinucleotide (NAD) in the context of aging and mitochondrial function has turned into a fairly energetic area of study. NAD is a crucial element in the mitochondrial production of the chemical energy store molecule adenosine triphosphate (ATP), but levels decline with age for a variety of reasons, and this contributes to loss of mitochondrial function. The characteristic changes in gene expression that take place with age lead to reduced production and recycling of NAD via various pathways. Further, CD38 acts to break down NAD and levels of CD38 increase with age.

Why does CD38 production increase with age? Research suggests that this is a consequence of inflammatory signaling, the chronic inflammation of aging, driven in part by a growing burden of senescent cells, but also by molecular damage and debris that triggers similar immune reactions to those produced by infection.

In today's open access paper, researchers report on the effects of partial inhibition of CD38 in mice. In principle, the effect of this inhibition is to disconnect the relationship between inflammation and impaired mitochondrial function mediated by loss of NAD. This disconnection enables improved health and life span. This is an effect likely also possible to achieve via exercise, though not to the same magnitude when it comes to gains in maximum life span; in mice exercise only improves healthspan and medial life span.

Mouse lifespan is more plastic than that of humans in response to interventions that improve metabolism. It isn't clear at this point as to whether a 10-20% increase in lifespan should be seen as interesting. I am starting to lean towards reversal of age-related pathology in later life as a more interesting metric. Regardless of my opinion, clearly there will be considerable further effort devoted towards the clinical translation of ways to increase NAD levels or interfere in the activities of CD38. We shall see how well it does in humans at the end of the day, with structured exercise programs as the bar to beat.

CD38 inhibitor 78c increases mice lifespan and healthspan in a model of chronological aging

NAD is a cofactor of oxidation-reduction reactions and is a substrate for enzymes involved in cellular homeostasis. NAD levels decrease with aging and progeroid states, which is associated with metabolic abnormalities and fitness decline. The NAD-consuming enzymes such as CD38 and PARP1 have been shown to play a major role in this process. The accumulation of CD38+-inflammatory cells decreases NAD levels in aging. The small molecule 78c is a specific and potent inhibitor of CD38 that boosts NAD levels, improves survival of progeroid mice, and ameliorates several metabolic, structural, and molecular features of aging. However, to date the effect of CD38 inhibition on natural aging and longevity has not been explored. Here, we demonstrate that 78c increases the lifespan and healthspan of naturally aged male mice.

When offered the food to young mice ad libitum, 78c significantly boosted NAD, validating the 78c treatment. We then placed 1-year-old C57BL/6 male and female mice on either a control or 78c diet and closely followed their healthspan and longevity. When both sexes were grouped, treatment with 78c significantly improved longevity, with a maximal survival increase of 9%. When analyzing survival for males and females separately, a sex-specific effect of 78c was observed. The 78c-treated males had a 17% increase in median survival and a 14% increase in maximal lifespan compared with control. In females, no significant survival benefit was observed

We then evaluated the effect of 78c on the frailty in a cohort of old male mice. Frailty scores were derived from clinical examination. Changes in frailty index after 3 months were plotted in comparison with the baseline index. All animals in the control group had a significantly higher frailty index than that was 3 months earlier. By contrast, 78c showed a protection against age-related frailty increase.

Aging of the Intestinal Barrier as a Driving Cause of Chronic Inflammation
https://www.fightaging.org/archives/2022/03/aging-of-the-intestinal-barrier-as-a-driving-cause-of-chronic-inflammation/

Chronic inflammation is a feature of aging, and causes disruption of cell and tissue function throughout the body. Short term inflammation is a necessary feature of regeneration from injury and defense against pathogens, but when inflammatory signaling is maintained for the long term it becomes very harmful. The risk of suffering all of the common diseases of aging is strongly connected to raised inflammation. Given this, we might ask what causes age-related systemic inflammation, and thus where should the research community seek to intervene, in order to reverse this undesirable aspect of degenerative aging.

A growing burden of senescent cells is one noteworthy cause, actively encouraging inflammation via the senescence-associated secretory phenotype. The metabolic activity of excess visceral fat tissue is another. Disruption of the intestinal barrier is also an area of focus for the research community, and the subject of today's open access review paper.

The intestinal barrier is made up of mucus, epithelial cells connected by tight junctions that prevent the passage of unwanted pathogens and molecules, and patrolling immune cells, intended to maintain a separation between the gut and tissues surrounding the gut. Unfortunately, like all structures and systems in the body, the barrier becomes dysfunctional with age. The result is greater inflammation, as unwanted materials leak into tissue.

The Intestinal Barrier Dysfunction as Driving Factor of Inflammaging

In recent years, the function of the intestinal barrier has received increasing scientific attention as more and more intra- and extra-intestinal diseases, such as irritable bowel syndrome, inflammatory bowel diseases such as Crohn's disease, type 1 diabetes, colorectal cancer, acute inflammation-related diseases such as sepsis, and allergic diseases, were found to be associated with a dysfunctional intestinal barrier. The results of various animal studies demonstrated a link between intestinal barrier dysfunction and aging. For instance, aged monkeys had poorer intestinal barrier function, increased systemic inflammation, and higher microbial translocation compared to young animals. In Drosophila models, intestinal barrier dysfunction has been shown to predict the approaching death of flies.

In this review, we want to explore whether intestinal barrier dysfunction and the accompanying alterations to the intestinal microbiota composition are driving factors for the increasing proinflammatory status during aging known as inflammaging. Inflammaging was first described as a combination of a reduced ability to deal with stressors and the resulting increase in proinflammatory milieu. More recently, inflammaging was defined as a "chronic, sterile, low-grade inflammation" that occurs during aging. A similar concept is metaflammation, describing a metabolically driven inflammation caused by nutrient excess.

Due to the major role of the intestinal barrier in preventing bacterial toxins and pathogens from the intestinal lumen entering into circulation, an impaired barrier function or even minor changes in the regulation of the epithelial, microbial, biochemical, or immunological barrier might contribute to aging-associated decline as well as disease development.

The alterations found at the level of intestinal microbiota composition and intestinal barrier function in aging have been proposed to be interlinked with aging-associated decline in other organs, such as the liver. Due to its anatomical location receiving a more or less 'unfiltered' blood from the gut, the liver is confronted not only with nutrients, but also many xenobiotics, as well as bacterial toxins and metabolites stemming from the intestinal microbiota, along with endocrine mediators. This allows for a rather direct communication between the gut and the liver.

In summary, the gastrointestinal epithelial barrier, with its multiple layers and its various function, is affected by the physiological aging process. However, as its role in healthy aging or disease development becomes increasingly evident, attempts to restore the barrier function, e.g., through modulation via microbiota modifications, supplementing strains such as Lactobacillus plantarum or their metabolites, are of special interest. Besides microbiota modulation through probiotic strains or postbiotics, the current and future treatment of epithelial barrier dysfunction could include nutritional interventions and also bioactive pharmaceutical molecules, biologicals, or mucoprotectants.

The Effective Altruism Community on the Merits of Philanthropy to Advance Cryonics for Brain Preservation
https://www.fightaging.org/archives/2022/03/the-effective-altruism-community-on-the-merits-of-philanthropy-to-advance-cryonics-for-brain-preservation/

The effective altruism community is concerned with practical utilitarianism and efficiency in the matter of philanthropy. This can range from avoidance of inefficient charities, and the infrastructure needed for more people to find out which organizations are in fact efficient in their chosen field, to comparisons between philanthropic causes with the aim of finding the greatest gain for a given donation. Since the greatest cause of human suffering, by far, is aging, it is naturally the case that effective altruists frequently discuss rejuvenation biotechnology. A related field is that of the cryonics industry and cryopreservation, low-temperature storage of at least the brain on death, to save lives that cannot otherwise be saved because rejuvenation technologies will not arrive rapidly enough.

A cryopreserved individual is only clinically dead. The data of the mind still exists, the tissue structure still exists. It is possible to envisage in great detail the future technological capabilities needed to bring a cryopreserved patient back to active life - and people have, such as in the recently published Cryostasis Revival. Given the choice between tens of millions of minds lost to oblivion every year, or taking a chance of preservation, it seems obvious that cryopreservation should be far more widespread and better supported than it is. Yet this is an argument yet to be accepted by anything more than a small, fringe community.

Today I'll point out an opinionated summary of discussions on cryopreservation from the effective altruism community. The cryonics industry is small and lacks funding for efficient progress towards the virtuous cycle of technological advances that convince people this is real, greater attention, rising membership, and thus more funding for further technological advances. This is the type of problem that philanthropy excels at solving, provided those directing the funding know what they are doing. Clear and demonstrable technological progress in reversible cryopreservation of organs, a capability that has immediate application to the transplantation industry, is an important goal that could be greatly accelerated by philanthropy, for example. Alas, many people have yet to be convinced that saving lives in this way is desirable, or that present approaches give a good enough chance of success to be funded.

Brain preservation to prevent involuntary death: a possible cause area

Note that prior effective altruism discussions primarily focus on cryonics, although I prefer the term brain preservation because it is also compatible with non-cryogenic methods and anchors the discussion around the preservation quality of the brain. I'm not discussing whether individuals should sign themselves up for brain preservation, but rather whether it is a good use of altruistic resources to preserve people and perform research about brain preservation. It seems to me that:

(a) Most current technical arguments against brain preservation, to the extent that there are any at all, don't grapple with the possibility of structural inference. Because of the correlated nature of structural information in the brain, it is likely that there are numerous topological maps of the biomolecule-annotated connectome that could retain the information needed for long-term memories. Even if many of these maps were damaged or destroyed by aspects of the brain preservation procedure, if at least one could still be inferred, then the information content would still be present.

(b) Most extant arguments in the effective altruism community against brain preservation as a cause area don't grapple with QALY improvement/extension, and for unclear reasons treat humans as replaceable units, neglecting relational and psychological factors. If people think humans are replaceable, I think they should justify this, and also consider whether they are being consistent about it.

(c) With today's methods, brain preservation may already be among the best altruistic investments available from a QALY improvement/extension perspective, given reasonable estimates about the probability of success.

(d) With more research, substantially cheaper methods for structural brain preservation could potentially be developed, which could further improve the cost/benefit calculus. With more research, our uncertainty about different aspects of the brain preservation project could also be better clarified.

As a result of the above, and given its neglectedness, I think brain preservation for the prevention of involuntary death is one of the best areas for people interested in helping others to work in. I also think it is a great place for people who are interested in helping others to donate money. If you disagree, I would love to hear from you why that is. If you agree, I would love to discuss with you practical topics of how to best improve the field. Thanks for reading!

Towards Enhanced Mitochondrial Fission to Improve Mitochondrial Function in Later Life
https://www.fightaging.org/archives/2022/03/towards-enhanced-mitochondrial-fission-to-improve-mitochondrial-function-in-later-life/

Mitochondrial function declines with age throughout the body. One of the better explored lines of investigation of this phenomenon focuses on changes in gene expression causing a reduction in mitochondrial fission, leading to impaired mitophagy, in turn leading to a build up of worn and dysfunctional mitochondria. Mitochondria are the descendants of ancient symbiotic bacteria, and they divide (fission) and join together (fusion) like bacteria. Mitophagy is the quality control mechanism responsible for removing damaged mitochondria, and it requires mitochondrial fission in order to operate efficiently, as larger mitochondria are more resistant to mitophagy.

Are there ways to provoke a restoration of youthful levels of mitochondrial fission and thus mitophagy? In one sense yes, in that all of the established approaches to boosting mitochondrial function improve the situation to some degree, such as NAD+ upregulation and mitochondrially targeted antioxidants. In another sense no, as none of those options are definitively better than regular exercise. In a final sense yes, in that researchers have identified various proteins that change in expression with age, affecting mitochondrial fission. It is a long road from identifying a protein to finding a small molecule drug that can safely affect its expression, however, and gene therapies to precisely achieve this sort of outcome throughout the body are still not a going concern.

Today's research materials are an example of this type of work, investigating the mechanisms of mitochondrial fission in search of targets that might improve it in old tissues. It remains to be see what the next generation of therapies aimed at improving mitochondrial function will look like, but it is plausible that transplantation of functional mitochondria, an approach already in preclinical development in several companies, will prove to be a good way to work around the need for a great deal of further research and understanding of mechanisms.

Researchers show protein controls process that goes awry in Parkinson's disease

As scientists work toward finding a cure for Parkinson's disease, one line of research that has emerged focuses on mitochondria, the structures within cells that make energy. The health of those structures is maintained through a quality control system that balances two opposite processes: fission - one mitochondrion splitting in two - and fusion - two becoming one. When there's a problem with fission, that system is thrown out of balance. The consequences can include neurodegenerative diseases, such as Parkinson's disease, and other serious conditions.

A new study found that a protein in humans called CLUH acts to attract Drp1 to mitochondria and trigger fission. In experiments with fruit flies that were genetically engineered with an analog for Parkinson's disease, the team showed that damage from the disease could be reversed by increasing the amount of a protein that scientists call "clueless," which is the fruit fly equivalent of CLUH. "With a critically important pathway such as Drp1, there might be multiple proteins we could use to intervene and ultimately control Parkinson's disease. When we modified clueless in flies, symptoms analogous to Parkinson's disease improved substantially."

The team further showed that both clueless in flies and CLUH in human cells recruit free-floating Drp1 from within a cell to attach to receptors on the surface of mitochondria. In addition, the researchers discovered that CLUH in human cells helps translate the genetic instructions found in messenger RNA into the protein for Drp1 receptors on the surface of mitochondria. More available Drp1 receptors means that more Drp1 can be recruited in order to trigger fission.

Clueless/CLUH regulates mitochondrial fission by promoting recruitment of Drp1 to mitochondria

Mitochondrial fission is critically important for controlling mitochondrial morphology, function, quality and transport. Drp1 is the master regulator driving mitochondrial fission, but exactly how Drp1 is regulated remains unclear. Here, we identified Drosophila Clueless and its mammalian orthologue CLUH as key regulators of Drp1. As with loss of drp1, depletion of clueless or CLUH results in mitochondrial elongation, while as with drp1 overexpression, clueless or CLUH overexpression leads to mitochondrial fragmentation.

Importantly, drp1 overexpression rescues adult lethality, tissue disintegration, and mitochondrial defects of clueless null mutants in Drosophila. Mechanistically, Clueless and CLUH promote recruitment of Drp1 to mitochondria from the cytosol. This involves CLUH binding to mRNAs encoding Drp1 receptors MiD49 and Mff, and regulation of their translation. Our findings identify a crucial role of Clueless and CLUH in controlling mitochondrial fission through regulation of Drp1.

A Taxonomy of Degree of Effort in Undertaking Interventions to Slow or Reverse Aging
https://www.fightaging.org/archives/2022/04/a-taxonomy-of-degree-of-effort-in-undertaking-interventions-to-slow-or-reverse-aging/

The urge to create taxonomies is very human, almost reflexive. We make lists, divide things up into buckets and categories. I'm not entirely convinced that there is yet the need to do this when it comes to personal efforts to slow or reverse aging, but that opinion certainly isn't going to stop people from publishing their thoughts on the matter. Today's open access paper is an example, in which a few arbitrary lines in the sand are drawn, and the spectrum of present day efforts to live longer is divided into five broad categories.

The one point that makes it, I think, hard to take any given taxonomy seriously is that we do not yet know how well the various options presently on the table perform in humans. There is reasonable support for the supposition that anything to do with stress response upregulation, such calorie restriction mimetic therapies, may be beneficial. Even if robustly so, however, as a strategy it is likely not going to be much better than good lifestyle choices. Some of those calorie restriction mimetics are unimpressive even given that caveat, such as aspirin and metformin. Similarly there is reasonable support for senolytics that clear senescent cells to be a very desirable medical technology, capable of much more than lifestyle choices can achieve.

It will be years yet before any of these suppositions are validated in human trials to the satisfaction of conservative minds, however, and years more before researchers can put actual numbers to the effects on human life span, given our length of life. Thus any taxonomy that takes into account efficacy might be premature. Still, we have to make decisions about which strategies to pursue in some way.

The intervention on aging system: A classification model, the requirement for five novel categories

The longevity industry has now entered a new era, where various longevity technologies are being used by a growing cohort of subjects worldwide. As humanity enters this new era, subjects and their healthcare advisors, even employers such as military or insurance companies may require a classification system to assist in understanding what therapies should be implemented (or avoided) at what time during life. A simplistic classification system with five classes enables the public to easily see where they sit on a mortality scale and may provide motivation to change their lifestyle. This system is inversely proportional to mortality: the higher your class, the more probable you are to develop disease or undergo loss of life.

Type V - The Type 5 category perform rudimentary functions to maintain life, such as washing hands and using seatbelts in cars; however, their diet includes fast food and occasional healthy food, these subjects may hold excessive weight, and overall, they do very little to extend their life or health span. Mortality Risk - Probable.

Type IV - The Type 4 demographic exercise and eat relatively healthy and may use health supplements. Type 4's attempt to navigate away from toxins such as cigarettes, perform weight management, and may restrict or abstain from alcohol though do not implement any emerging or significant longevity technologies or regimes such as fasting or clean plant-based diets. Mortality Risk - Moderate.

Type III - The Type 3 class is proactive in using anti-aging technologies, they actively seek and study longevity for increased awareness, they use nicotinamide adenine dinucleotide precursors to maintain cellular metabolism and foods specifically known for their anti-aging properties, they possibly practice fasting, use fasting mimetics, exercise and are lean or muscular, target a more epigenetic diet, and steer clear of any biological insults. Mortality Risk - Unlikely.

Type II - The Type 2 cohort implement a strict longevity lifestyle that is very similar to Type 3's; however, Type 2's also implement early disease prevention strategies such as whole genome sequencing, whole exome sequencing, gene panel, single gene testing, and methylation analysis to garner data on their disease predisposition and penetrance. Other testing such as glycomic testing, blood plasma, and proteomic testing and other biomarkers that can assist in predicting and in some cases preventing disease are also used. Mortality Risk - Low.

Type I - Type 1's encompass everything that Type 2's perform; however, Type 1's have achieved a status of disease prevention and developed strategies to prevent further biological decay through various lifestyle decisions, including full spectrum diagnostic services, gene editing, and tissue reprogramming, and immune system or thymic rejuvenation to ensure high resistance to disease and dysfunction.

The scale shown here clearly demonstrates that there are various stages to longevity management that are completely distinguishable between one another. A classification system such as this also paves the way for governments to set goals and targets for their aging populations. Even though Type I status is not yet achievable, the scale intentionally includes this category, not only for future use, but as a symbol for humanity's scientific vision and quest to deliver a disease-free and much healthier society.

On Killing Senescent Cells with Natural Killer Cells
https://www.fightaging.org/archives/2022/03/on-killing-senescent-cells-with-natural-killer-cells/

One comparatively unexplored path to clearing senescent cells from the aged body is to coerce portions of the immune system into working harder. In youth, the immune system is adept at removing senescent cells, and does so at a fast enough page to prevent accumulation. In old age, this process slows down. Here, researchers report on an in vitro demonstration of the potential for natural killer cells to clear senescent cells, marking their function as a potential target for the development of novel senolytic therapies capable of rejuvenation through the selective removal of senescent cells. Deciduous Therapeutics is a startup biotech company currently pursuing this path.

Previous experiments have shown that natural killer (NK) cells are partially responsible for the clearance of senescent cells from the human body. While some senescent cells have ways of avoiding detection and clearance, NK cells are attracted to certain parts of the senescence-associated secretory phenotype (SASP), which trigger them to kill the cells expressing it. Techniques are being developed to use this senolytic ability of NK cells as a potential therapy.

After taking NK cells out of whole blood, researchers sought to change the distribution of these cells. NK cells express different amounts of CD56 and CD16. NK cells that express high CD56 but low CD16 are immature and secrete interferon-γ; NK cells with low CD56 and high CD16 are responsible for cytotoxicity: the actual killing of other cells. The enrichment process, which involved activating the cells through the cytokine IL-2, substantially increased the percentages of both of these cell types.

These enriched cells were found to be very good at selectively eliminating senescent cells after 16 hours. In an experiment with one NK cell for every senescent cell, 15% of normal fibroblasts and 43% of senescent fibroblasts died. These numbers remained largely the same regardless of how senescence was induced, and endothelial cells yielded similar results to fibroblasts. Doubling or tripling the number of NK cells did kill more senescent cells; however, it also increased the number of normal cells being killed in the process. Therefore, instead of using more NK cells, the researchers increased the time in co-culture; while the number of normal fibroblasts dying remained low, only 10% of senescent cells survived after four days' exposure to fresh, enriched NK cells.

An Example of a Very Targeted, Narrow Improvement of Immune Function in Aged Individuals
https://www.fightaging.org/archives/2022/03/an-example-of-a-very-targeted-narrow-improvement-of-immune-function-in-aged-individuals/

There are many potential approaches to interfere in the sweeping age-related chances to immune function. Of these, many stem from epigenetic changes characteristic of age, causing dysregulation via too much or too little production of a given protein, rather than more structural issues relating to reduced production of immune cells and increasing wear and tear of populations of immune cells lacking reinforcements. In this arena, a more efficient small molecule drug discovery process can allow for incremental improvement in immune function, assuming one can find a single point of intervention that has a high yield outcome in one or more populations of immune cells.

As we age, a biochemical pathway involving the signaling molecule PGD2 becomes more active, impairing immunity in two major ways: First, antigen-presenting cells called dendritic cells migrate less efficiently, slowing the adaptive T-cell and antibody responses. Second, white blood cells called neutrophils infiltrate infected tissues more aggressively, leading to damaging inflammation. Thus, the aged immune system is both slower to respond to new infections and more likely to overreact once it does mount a response. Bioage's drug BGE-175 inhibits this pathway by blocking the interaction between PGD2 and its receptor, a protein called DP1.

In the study, daily doses of BGE-175 protected aged mice from a lethal dose of SARS-CoV-2, the virus that causes COVID-19. Ninety percent of mice that received the drug survived, whereas all untreated control mice died. BGE-175 treatment was initiated two days after infection, when the mice were already ill, a time-frame relevant to real-life clinical situations in which patients would receive medication only after becoming symptomatic.

BGE-175 is currently in a Phase 2 clinical trial to test whether it can prevent disease progression and mortality in older patients hospitalized with COVID-19. "The promising preclinical data in this paper show that BGE-175 almost completely protects aged mice from lethality in a compelling model of human COVID-19. By reversing age-related declines in critical immune mechanisms, BGE-175 could allow older patients to more effectively fight off this disease."

Mitophagy Protein BNIP3 is Protective Against Inflammation and Muscle Aging
https://www.fightaging.org/archives/2022/03/mitophagy-protein-bnip3-is-protective-against-inflammation-and-muscle-aging/

Mitophagy is the cellular maintenance process responsible for removal of damaged mitochondria, the vital power plants of the cell. With age, mitophagy becomes less effective, allowing mitochondrial function to decline, an important contribution to age-related degeneration in energy-hungry tissues such as muscle and the brain. A variety of dysfunctions contribute to this issue. Many arise from age-related changes in gene expression, such as loss of production of proteins necessary for mitochondrial fission, leading to larger mitochondria that are resistant to mitophagy. Researchers here focus on the effects of the BNIP3 protein on mitophagy and mitochondrial function, as well as downstream effects on inflammation and loss of muscle mass and strength with age.

Sarcopenia is one of the main factors contributing to the disability of aged people. Among the possible molecular determinants of sarcopenia, increasing evidences suggest that chronic inflammation contributes to its development. However, a key unresolved question is the nature of the factors that drive inflammation during aging and that participate in the development of sarcopenia. In this regard, mitochondrial dysfunction and alterations in mitophagy induce inflammatory responses in a wide range of cells and tissues. However, whether accumulation of damaged mitochondria in muscle could trigger inflammation in the context of aging is still unknown.

Here, we demonstrate that BNIP3 plays a key role in the control of mitochondrial and lysosomal homeostasis, and mitigates muscle inflammation and atrophy during aging. We show that muscle BNIP3 expression increases during aging in mice and in some humans. BNIP3 deficiency alters mitochondrial function, decreases mitophagic flux and, surprisingly, induces lysosomal dysfunction, leading to an upregulation of TLR9-dependent inflammation and activation of the NLRP3 inflammasome in muscle cells and mouse muscle. Importantly, downregulation of muscle BNIP3 in aged mice exacerbates inflammation and muscle atrophy, and high BNIP3 expression in aged human subjects associates with a low inflammatory profile, suggesting a protective role for BNIP3 against age-induced muscle inflammation in mice and humans.

Taken together, our data allow us to propose a new adaptive mechanism involving the mitophagy protein BNIP3, which links mitochondrial and lysosomal homeostasis with inflammation and is key to maintaining muscle health during aging.

Inflammatory Changes in Bone Marrow as a Precursor to Atherosclerosis
https://www.fightaging.org/archives/2022/03/inflammatory-changes-in-bone-marrow-as-a-precursor-to-atherosclerosis/

Atherosclerosis is in part an inflammatory condition, drive by the chronic inflammation of aging. It arises from dysfunction in the macrophage cells responsible for clearing out lipids from blood vessel wall, and inflammatory signaling makes those macrophages less able to perform that maintenance. There are other issues affecting the macrophages, not least of which being that they become overwhelmed by the large amount of cholesterol present in established atherosclerotic lesions, but inflammation is a noteworthy contribution to the problem.

The association between inflammation and atherosclerosis is well established, and mechanistic studies have demonstrated that inflammation is an essential mediator of all stages of atherosclerosis, from initiation to progression and the development of thrombotic complications. Circulating immune cells play a critical role in the build-up of atherosclerotic plaques by adhering to activated endothelium and infiltrating the arterial wall to become lesional cells. This association has led to the study of various anti-inflammatory therapies in the last years.

The bone marrow (BM) is the primary site of haematopoiesis, and the proliferation and migration of haematopoietic progenitors are regulated by various physiological and pathological stimuli. Experimental studies suggest that increased BM haematopoietic activity may be a central link between cardiometabolic risk factors and exacerbated inflammation in atherosclerosis. In mice, hypercholesterolaemia and low HDL-cholesterol levels associated with elevated haematopoietic activity with increased monocytosis and neutrophilia. Hypertension, driven by an overactive sympathetic activation, deteriorates haematopoietic cell niche in the BM which can contribute to atherosclerosis. In humans, it has been suggested that chronic stress accelerates haematopoiesis, giving rise to higher levels of inflammatory cells that might contribute to the atherosclerotic process. In addition, haematopoietic stem cell division rates are increased in subjects with atherosclerosis, and it has been suggested that the haematopoietic system might be chronically affected in these subjects.

However, human data to support this association are sparse. Our purpose was to study the association between cardiovascular risk factors, BM activation, and subclinical atherosclerosis. Whole body vascular 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI) was performed in 745 apparently healthy individuals (median age 50.5) from the Progression of Early Subclinical Atherosclerosis (PESA) study. Bone marrow activation (defined as BM 18F-FDG uptake above the median maximal standardized uptake value) was assessed. Systemic inflammation was indexed from circulating biomarkers.

Bone marrow activation was significantly associated with high arterial metabolic activity (18F-FDG uptake). The co-occurrence of BM activation and arterial 18F-FDG uptake was associated with more advanced atherosclerosis, i.e. plaque presence and burden.

Lifelong Exercise Preserves Muscle Stem Cells
https://www.fightaging.org/archives/2022/03/lifelong-exercise-preserves-muscle-stem-cells/

Researchers here assess the state of muscle stem cells and neuromuscular junctions, both known to decline in function with advancing age. This leads to sarcopenia, the loss of muscle mass and strength. This is a universal phenomenon, but some people are more affected than others. Many underlying mechanisms contribute to these issues, with the chronic inflammation of aging being an important one, but a perhaps surprising degree of muscle aging in our modern world is a consequence of lack of exercise. The study noted here is an example of this point, showing the degree to which fitness slows core aspects of muscle degeneration.

Muscle fibre denervation and declining numbers of muscle stem (satellite) cells are defining characteristics of ageing skeletal muscle. The aim of this study was to investigate the potential for lifelong recreational exercise to offset muscle fibre denervation and compromised satellite cell content and function, both at rest and under challenged conditions. Sixteen elderly lifelong recreational exercisers (LLEX) were studied alongside groups of age-matched sedentary (SED) and young subjects. Lean body mass and maximal voluntary contraction were assessed, and a strength training bout was performed. From muscle biopsies, tissue and primary myogenic cell cultures were analysed by immunofluorescence and RT-qPCR to assess myofibre denervation and satellite cell quantity and function.

LLEX demonstrated superior muscle function under challenged conditions. When compared with SED, the muscle of LLEX was found to contain a greater content of satellite cells associated with type II myofibres specifically, along with higher mRNA levels of the beta and gamma acetylcholine receptors (AChR). No difference was observed between LLEX and SED for the proportion of denervated fibres or satellite cell function, as assessed in vitro by myogenic cell differentiation and fusion index assays. When compared with inactive counterparts, the skeletal muscle of lifelong exercisers is characterised by greater fatigue resistance under challenged conditions in vivo, together with a more youthful tissue satellite cell and AChR profile. Our data suggest a little recreational level exercise goes a long way in protecting against the emergence of classic phenotypic traits associated with the aged muscle.

Considering Stem Cells in the Context of Cancer and Aging
https://www.fightaging.org/archives/2022/03/considering-stem-cells-in-the-context-of-cancer-and-aging/

Is it useful to think of cancer as a stem cell disease, a condition that (largely) arises because stem cells become dysfunctional? The evidence seems to suggest that at least some cancers arise from somatic cells taking on stem cell properties, while a body of work indicates that at least some cancerous tissues are supported by small populations of cancer stem cells that might be targeted for destruction. Here researchers are interested in the bigger picture, the nature of the relationship between stem cell function, stem cell resilience, cancer, and aging. In an era that will soon enough seen the widespread use of regenerative medicine and rejuvenation therapies that, by their nature, will increase stem cell function in older people, it is perhaps worth thinking about how cancer risk fits into all of this.

A stem-cell theory of cancer predicates that not only does the cell affect the niche, the niche also affects the cell. It implicates that even though genetic makeup may be supreme, cellular context is key. When we attempt to solve the mystery of a long cancer-free life, perhaps we need to search no further than the genetics and epigenetics of the naked mole-rat. When we try to unlock the secrets in the longevity and quality of life, perhaps we need to look no further than the lifestyle and habits of the super centenarians. We speculate that people with Down's syndrome and progeria age faster but have fewer cancers, because they are depleted of stem cells, and, as a consequence, have fewer opportunities for stem cell defects that could predispose them to the development of cancer. We contemplate whether these incredible experiments of nature may provide irrefutable evidence that cancer is a stem-cell disease-fewer aberrant stem cells, fewer cancers; no defective stem cells, no cancer.

A stem-cell theory of aging and cancer reiterates a fundamental oncological principle: although genetic makeup may be pivotal, cellular context is paramount. When the genome and epigenome that regulate aging and malignancy are also stemness genes and stem-like properties, they reaffirm the key role that stem-cell quality and quantity play in longevity and cancer. We suspect that long-lived, cancer-spared mammals maintain a youthful genome and epigenome because they are equipped with a larger and healthier pool of stem cells. We contemplate that people with Down's syndrome and progeria age faster but have fewer cancers because they are depleted of stem cells and therefore have fewer opportunities for stem-cell defects that render one prone to cancer formation.

Therefore, the benefit of longevity needs to be balanced against the risk of malignancy. Intuitively, how we manage to conserve stemness and delay senescence is key.

The Senescence-Associated Cell Transition and Interaction (SACTAI) Model of Tissue Aging
https://www.fightaging.org/archives/2022/03/the-senescence-associated-cell-transition-and-interaction-sactai-model-of-tissue-aging/

Senescent cells are created and destroyed constantly throughout life, but their numbers accumulate with age, a growing imbalance that is probably primarily caused by immune system aging. The immune system is responsible for removing those senescent cells that do not undergo programmed cell death, but it becomes ever less competent with age. A lingering population of senescent cells is clearly responsible for causing significant harm to cell and tissue function, largely via the secretion of inflammatory, pro-growth factors. Here, researchers think a little more deeply about how this harm progresses.

Here, based on recent research evidence from our laboratory and others, we propose a mechanism - Senescence-Associated Cell Transition and Interaction (SACTAI) - to explain how cell heterogeneity arises during aging and how the interaction between somatic cells (SomCs) and senescent cells, some of which are derived from aging somatic cells, results in cell death and tissue degeneration. Recent genomic analysis reveals a remarkable heterogeneity of cell types during aging. Such cell heterogeneity gives rise to not only senescent cells but also other types of cells including progenitor and stromal cells.

Adult mesenchymal stem cells (MSCs) constitute a small percentage of cells responsible for repair upon tissue damage. The increase in senescent cells is tightly associated with repeated activation of adult MSCs, where they reach replication capacity and become senescent. In response to stress signals, differentiated SomCs may lose their identity and de-differentiate into MSC-like cells for repair. Such epigenetically re-programmed MSCs are subject to cell senescence triggered by replicative, mechanical, and inflammatory stress signals. Although in small numbers, senescent MSCs manifest the senescence-associated secretory phenotype (SASP), spread inflammation, and signal surrounding somatic cells in the tissue microenvironment. Thus, senescent MSCs may accumulate during aging by cell proliferation, transition, and senescence, and accelerate catabolism and death of somatic cells through cell interactions. Important signaling molecules mediating the SACTAI process include pro-inflammatory cytokine IL-1β, IL-6, IL-8, growth factor TGF-β, and morphogen Sonic Hedgehog, which at least partially overlap with SASPs.

SACTAI is a proposed two-step mechanism for aging-associated tissue degeneration and somatic cell death. In the first step, a few adult SomCs, in response to mechanical, inflammatory, or replicative stress signals, undergo proliferation, MSC transition, and senescence, resulting in senescent MSCs (snMSCs). This cell transition and senescence process results in a heterogenous cell population, which enables heterotypic cell interactions with each other. During the second step, snMSCs interacts with SomCs via SASPs. Such cell senescence-associated signaling contributes to cell death and tissue degeneration in age-related diseases. The newly discovered SomC transition to snMSC during aging may explain the fibrosis, abnormal ossification (calcification), and inflammaging phenotypes often associated with aging tissues. The identification of the multi-step mechanism of SACTAI provides an opportunity to develop potential drugs to intervene during different stages of age-related disease pathogenesis.

In Replicative Senescence, Cells Become Senescent Slowly as Telomeres Shorten
https://www.fightaging.org/archives/2022/03/in-replicative-senescence-cells-become-senescent-slowly-as-telomeres-shorten/

Telomeres are caps of repeated DNA sequences at the ends of chromosomes. Telomere length is reduced with each cell division, and when telomeres become too short cells become senescent and either undergo programmed cell death or are removed by the immune system. This ensures cell turnover in tissues, and acts to reduce the risk of cell lineages becoming damaged enough to become cancerous.

Researchers here present evidence for the onset of this replicative senescence to be a slow process, changes assembling and growing as telomeres become shorter. The implication is that while senescent cells are known to be harmful when they accumulate with age, perhaps the burden of pre-senescent cells in old tissues is also meaningfully harmful. Whether or not this is the case has yet to be determined; the challenge is never in identifying a mechanism, the challenge lies in determining how important it is.

In 1961, researchers discovered that human fibroblast cells cultured in the laboratory could only divide a limited number of times, after which they stopped multiplying but remained metabolically active. This state was termed replicative senescence and was found to occur in a range of cell types. Further research revealed that senescence is caused by the shortening of caps, or 'telomeres', on the end of chromosomes. Every time a cell divides, its telomeres shrink until they reach a critical length that stops the cell from multiplying. New evidence showed that senescence is induced by cell stress as well as successive divisions, and that the number of senescent cells increases as tissues age.

Despite almost 60 years of research, many questions still remain about senescence; for instance, what happens to cells as they transition in to the senescent state? How does their metabolism change during this shift, and do they take on a new cell identity? Now researchers report the results of experiments that exquisitely profile the roadmap cells take on their path to senescence.

The team used a new experimental design to survey the entire genome and repertoire of RNAs, proteins, and metabolites present in fibroblasts cultured in the laboratory. These patterns were traced over time as the cells grew until they stopped dividing. The data revealed that RNAs known to be expressed in fully senescent cells progressively accumulate throughout the cell cycle. This suggests that senescent cells in vivo may be slowly amassing these features, but not yet expressing the classic biomarkers associated with the end-point of senescence, such as the beta-galactosidase enzyme.

The findings suggest that cells gradually acquire a number of changes on the path to replicative senescence: they express different genes, rewire their metabolic reactions and take on a new identity similar to mesenchymal cells. Previous studies have shown that removing senescent cells can increase the health- and life-span of mice. Therefore, interventions that target these early changes could help improve the well-being of individuals by stopping the cascade of events that lead to replicative senescence.

A Review of Some of What is Known of Aging in Liver Tissue
https://www.fightaging.org/archives/2022/04/a-review-of-some-of-what-is-known-of-aging-in-liver-tissue/

Autophagy is the name given to a collection of cellular housekeeping processes that recycle damaged and otherwise unwanted proteins and structures in the cell. Increased autophagy is a common feature of interventions that alter metabolism and slow aging in short-lived species. This is well studied in the context of calorie restriction, and is likely an important mechanism in mTOR inhibition, such as via rapamycin. Still, the only really impressive results produced via upregulation of autophagy to date are in the liver, starting with the use of LAMP2A as a target to improve operation of the lyosomal portion of autophagy in aged animals. In that context, it is interesting to take a look at what is known of aging at the detail level in liver tissue.

During aging, the liver undergoes a series of degenerative changes. Briefly, it presents a progressive decrease in functional liver mass, thus reducing its functional reserve, making it more difficult to maintain homeostasis and vulnerable to external stress or damage. Till now, the mechanisms underlying liver aging still remain unclear. As we known, the main causes of aging are DNA damage, telomere shortening, epigenetic alterations, and impairment of proteostasis.

The aged liver is usually accompanied with failure of regeneration, metabolic dysfunction, redox imbalance, and development of chronic or malignant liver diseases. The impairment of regenerative capacity in the aged liver is affected by both intracellular factors and extracellular factors. Intriguingly, we may be able to recover their regenerative capacity via changing a microenvironment for the senescent hepatocytes. The aging-related alterations in the liver form a unique microenvironment and affect a series of physiological processes. Moreover, this unique microenvironment may function as a vital role that causes the liver to become susceptible to chronic diseases or tumors. For instance, it affects the fate of hepatocytes and promotes neoplastic development. Moreover, hepatocytes in this microenvironment are more susceptible to ischemia/reperfusion (I/R) injury.

Of particular interest is the way to effectively eliminate the effects of aging and reverse the unique aging microenvironment in the aged liver. Modulation of autophagy could function as an effective strategy for reversing aging in the liver. Autophagy mainly functions as a cytoprotective role in liver diseases. Modulation of autophagy could markedly alleviate aging-related liver injury, promote liver regeneration, block I/R induced injury, and reverse the aging microenvironment in the aged liver.

Senolytics as a Treatment for Intervertebral Disc Degeneration
https://www.fightaging.org/archives/2022/04/senolytics-as-a-treatment-for-intervertebral-disc-degeneration/

Degenerative disc disease is commonplace, and in recent years research has implicated the age-related accumulation of senescent cells in the onset and progression of this condition. Senolytic drugs to clear senescent cells may thus be a useful treatment. Existing senolytics, such as the dasatinib and quercetin combination, could be applied to many age-related conditions, since senescent cells and their inflammatory secretions produce broad negative effects on cell and tissue function. Unfortunately there is little funding and financial incentive for academic organizations to run clinical trials for even a significant fraction of these conditions.

Intervertebral disc degeneration (IVDD) refers to an age-related change that mainly occurs in the lumbar intervertebral disc and often precedes other age-related changes. During the process of IVDD, annulus fibrosis (AF), one of the important compositions of intervertebral disc, loses its original layer and toughness, and reticulated degeneration and hyalinization appear, while the percentage of water decreases in another component called nucleus pulposus (NP). As a result, the intervertebral disc loses its normal elasticity and tension.

Aging is the primary risk factor for the development of IVDD, which causes the accumulation of senescent cells in the intervertebral disc. Researchers have found that senescent NP cells play an important role in the initiation of IVDD. The number of senescent NP cells increased significantly during IVDD, suggesting the deleterious effect of senescent NP cells on the pathogenesis of IVDD. Recent studies have shown that senescent cells could secrete metabolic factors such as pro-inflammatory cytokines, matrix-degrading proteases, growth factors://en.wikipedia.org/wiki/Growth_factor">growth factors, and chemokines, which caused changes of the extracellular matrix (ECM). In addition, senescent cells can affect adjacent cells through paracrine signaling, thereby inducing the catabolism and inflammation in the microenvironment of intervertebral disc. The metabolic factors secreted by senescent cells are collectively named senescence-associated secretory phenotype (SASP).

In recent years, investigations on new drugs that target the process of senescence have become a new therapeutic strategy for the early prevention and latter treatment for degenerative diseases. Evidence suggest that whether through genetically modified strategy or chemotherapy, the elimination of p16INK4a senescent cells has been shown to significantly extend the healthspan in murine models. So, optimizing treatments to reduce senescence or eliminate senescent cells may exert positive effects on human health. Senolytic represents a wide range of drugs or small molecules that can selectively eliminate senescent cells. The application of senolytic drugs is a potential strategy for degenerative disease treatment, including IVDD.