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  • Interventions Targeting the Aging of the Gut Microbiome
  • Non-Alcoholic Fatty Liver Disease as the Marker of a Lifestyle that Shortens Life Span
  • BMP6 as a Target for Pro-Angiogenic Therapies
  • OneSkin Launches a Topical Senolytic Treatment
  • The Challenge of Achieving Healthy Human Longevity
  • Targeting NAD+ Metabolism for the Treatment of Cardiovascular Disease
  • Molecules Leaking from Damaged Muscle Fibers can Activate Muscle Stem Cells
  • Phosphate as an Agent of Accelerated Aging
  • Myokines Mediate the Effects of Exercise on Health
  • Chromatin Changes in the Aging of Stem Cells
  • miR-195 Promotes Blood-Brain Barrier Integrity by Suppressing TSP1 Activity
  • COVID-19 Is Only One of the Compelling Arguments for Developing the Means of Immune System Rejuvenation
  • Obese Individuals Have an Impaired Synaptic Plasticity Response
  • Cerebrovascular Disease Prevention as a Priority in Dementia Prevention
  • ELOVL2 in the Aging of the Eye

Interventions Targeting the Aging of the Gut Microbiome

Age-related changes to the microbial populations of the gut, the gut microbiome, appear important in the progression of aging. The effects on long-term health and risk of age-related conditions might be on a par with those of physical activity, and certainly overlap with those of diet. With ageing, beneficial microbes that produce metabolites (such as butyrate) that lead to better tissue function diminish in number, while harmful microbes that spur chronic inflammation grow in number. This may be due to loss of immune system competency, as the immune system gardens the gut microbiome, or it may be due to diminished intestinal barrier efficiency. Changes in diet characteristic of age may also play a role, but it is an open question as to the relative size of these and other potential contributing effects.

The research and medical community may not require a complete understanding prior to taking action, as it is quite clear from animal models that fecal microbiota transplantation from young to old reverses changes in the microbiome, improves health, and extends life span. Fecal microbiota transplantation is already practiced in human medicine, for conditions in which pathological bacteria overtake the intestine – conditions more commonly found in older people. Thus there is a comparatively short path to its use as a way to reverse ordinary, harmful age-related changes in the gut microbiome, given the will and funding to forge ahead.

Gut microbiota and old age: Modulating factors and interventions for healthy longevity

From a healthcare perspective, a longer life does not necessarily mean more health life-years. Unfortunately, aging often manifests itself negatively through frailty. Recent research has suggested that aging may be also associated with a different gut microbiota composition (i.e. a rearrangement) and with the increased presence of certain pathobionts, as compared to younger adults. This may be related to the heightened disease progression (and exposure to medication) and the decrease in immunocompetence in the older population. Most degenerative diseases are affected by our long-term dietary habits and lifestyle. Diet is also one of the most influential factors affecting our gut microbiota composition, diversity and function. Therefore, age-related dietary alterations could negatively impact the gut microbiota health in the older adults, and, consequently, their healthy longevity.

How aging affects the gut microbiota, the effects of the age-related changes on the health status of the host, and possible therapeutic approaches to counteract the negative aspects of dysbiosis have recently received considerable research interest. Although this research area has been expanding tremendously over the past years, there are still major gaps in our understanding of the functional interactions between the complex microbial community and the human host, especially at an advanced age. For example, which are the main factors which negatively influence our gut microbiota diversity and functions? Are they different in the older population as compared to younger adults? Are there specific microbiome signatures for longevity or are they rather reflective of health status? Are short-term effects (e.g. antibiotic exposure) as important as the long-term ones (e.g. food preferences), and which ones are more difficult to counterbalance? Are therapeutic interventions targeting the gut microbiota less effective or less safe in the older adults? Are these interventions suitable for entire populations, or should they be targeted individually (i.e. personalized modulation of the microbiota)?

Over the past two decades, numerous randomized clinical trials have been conducted in various target populations, including the older adults, to investigate the effectiveness of several therapeutic approaches impacting out gut microbiota and improving our health. Among these, supplementation of the human diet with beneficial microorganisms (probiotics), substrates to promote the proliferation of these beneficial microbes (prebiotics), or a combination of both (synbiotics) represent the most investigated health interventions.

Based on the results of several randomized clinical trials showing fecal microbiota transplantation (FMT) as a viable alternative treatment approach against C. difficile infection, current clinical guidelines recommend FMT for “patients with multiple recurrences of C. difficile infection who have failed appropriate antibiotic treatments (strong recommendation, moderate quality of evidence)”. C. difficile infection is known to affect the older population disproportionately, mainly due to immunosenescence, increased exposure to healthcare settings, and frequent use of antibiotics and proton-pump inhibitors. FMT proved to be a safe and effective treatment option for C. difficile infection in older adults.

Following the success in C. difficile infection treatment, the potential of FMT has also been investigated against Crohn’s disease, irritable bowel syndrome, cirrhosis, and even neurological and behavioral conditions. The results are promising, but still modest. One important aspect in the success of FMT is the diversity and the composition of the stool donor, which plays an essential role in restoring metabolic deficits in recipients.

Our gut microbiota is a dynamic ecosystem, which adapts continuously to changes in lifestyle, nutrition, hygiene, and exposure to medication. Establishing and maintaining positive interactions between us and our gut microbiota are essential for our health. The longer the exposure to certain stressors, the more significant the changes, which may explain why recent research has found that older populations have a less diverse microbiota than younger individuals, and more pathobionts. With advanced age, the prevalence of certain diseases increases as well, which can also contribute to an increased risk of frailty leading to microbiota dysfunctionalities, and therefore, to progression of other metabolic diseases.

Regarding older adults, and especially the residents of long-term care facilities, microbiota-targeted interventions should be made early and often, to attenuate the occurrence of critical conditions such as frailty. Any long-term medication exposure, and especially antibiotic treatments, should be followed by a microbiota restoration therapy, to prevent the occurrence of dangerous infections such as C. difficile and the proliferation of other opportunistic strains.

Non-Alcoholic Fatty Liver Disease as the Marker of a Lifestyle that Shortens Life Span

If you are overweight, then you will suffer a faster pace of aging, more age-related disease, greater lifetime medical costs, and an earlier death. The more excess weight and the longer that weight is held, the worse the outcome. In at least one sense, being overweight literally accelerates aging, increasing the pace at which harmful senescent cells accumulate in the body. These errant cells secrete signals that produce chronic inflammation, but this isn’t the only way in which visceral fat tissue causes unresolved, chronic inflammation, an unwanted overactivation of the immune system that disrupts metabolism and speeds the progression of age-related disease. Fat cells produce signals that mimic those of infected cells, and DNA fragments released from dying fat cells produce a similar outcome.

Whenever one looks at the relationship between mortality and metabolic diseases – such as non-alcoholic fatty liver disease, today’s topic – that are usually the product of being overweight, then one is looking at a proxy measure of the progression of mechanisms by which visceral fat tissue accelerates aging. Today’s research materials note that even mild non-alcoholic fatty liver disease is linked to increased mortality. This is because the most common cause of mild non-alcoholic fatty liver disease is for an individual to be meaningfully overweight, carrying excessive visceral fat tissue that disrupts metabolism and harms future prospects.

Even mild fatty liver disease is linked to increased mortality

Non-alcoholic fatty liver disease, NAFLD, is often caused by obesity and affects nearly one in four adults in Europe and the US. Earlier research has demonstrated an increased risk of death in patients with NAFLD. Now, researchers show that mortality increases with disease severity, but even mild fatty liver disease is linked to higher mortality. The researchers matched 10,568 individuals with biopsy-confirmed NAFLD to general population controls through Sweden’s comprehensive, nationwide registers. They found that all stages of NAFLD were associated with excess mortality risk, even early stages of disease. This risk was driven primarily by deaths from cancer (excluding liver cancer) and cirrhosis, while the risks of cardiovascular mortality or hepatocellular carcinoma (HCC) mortality were relatively modest.

Patients with NAFLD had a 93 percent increased risk of all-cause mortality, but the numbers varied with disease severity. The risk increased progressively from the mildest form of NAFLD (simple steatosis), to non-fibrotic steatohepatitis (NASH), to non-cirrhotic fibrosis, and to severe NAFLD with liver cirrhosis.

Even mild fatty liver disease is linked to increased mortality

This nationwide, matched cohort study included all individuals in Sweden with biopsy-confirmed NAFLD (1966 to 2017; n=10,568). NAFLD was categorised as simple steatosis, non-fibrotic steatohepatitis (NASH), non-cirrhotic fibrosis and cirrhosis. Using Cox regression, we estimated multivariable-adjusted hazard ratios (aHRs).

Over a median of 14.2 years, 4,338 NAFLD patients died. Compared with controls, NAFLD patients had significantly increased overall mortality (aHR=1.93). Compared with controls, significant excess mortality risk was observed with simple steatosis (aHR=1.71), non-fibrotic NASH (aHR=2.14), non-cirrhotic fibrosis (aHR=2.44) and cirrhosis (aHR=3.79). This dose-dependent gradient was similar when simple steatosis was the reference. The excess mortality associated with NAFLD was primarily from extrahepatic cancer (aHR=2.16), followed by cirrhosis (aHR=18.15), cardiovascular disease (aHR=1.35) and hepatocellular carcinoma (HCC) (aHR=11.12).

In conclusion, all NAFLD histological stages were associated with significantly increased overall mortality, and this risk increased progressively with worsening NAFLD histology. Most of this excess mortality was from extrahepatic cancer and cirrhosis, while in contrast, the contributions of cardiovascular disease and HCC were modest.

BMP6 as a Target for Pro-Angiogenic Therapies

Today’s research materials are focused on the fine details of angiogenesis, the formation of new blood vessels, and point to BMP6 as a potential target to increase or diminish that process. Angiogenesis is very well studied by the cancer community, in the context of how tumors subvert tissue signaling to support themselves via the generation of blood vessel networks. Angiogenesis is perhaps an underappreciated topic in the study of aging, however, and particularly with regard to the treatment of aging as a medical condition. There is a good argument to be made that the observed loss of capillary density in older individuals is an important aspect of degenerative aging, a downstream consequence of poorly understood chains of cause and effect, that in turn leads to disruption of blood pressure maintenance and feedback systems, and diminished delivery of nutrients to tissues throughout the body.

A few fairly blunt approaches to boosting angiogenesis have been demonstrated in mice. This is largely in the context of cardiovascular disease, however, trying to encourage the creation of additional larger blood vessels that can bypass areas of damage. Growing such additional blood vessels prior to a cardiovascular event would obviously be preferable, and this is a plausible goal for the future of medicine. One strategy is to mobilize hematopoietic and endothelial cells from the bone marrow, using much the same class of treatment that is employed to collect donor cells for hematopoietic stem cell transplantation. These cells are involved in angiogenesis, and when the vasculature is flooded with them, more angiogenesis takes place.

Effects on capillary density have yet to be assessed, unfortunately. This is a part of the field that merits greater attention. For example, an intriguing study showed that mouse life span is extended by a related class of hematopoietic cell mobilizing drug. The mechanism of action was left undetermined, however. It could as well be improved immune function via increased hematopoietic generation of immune cells as improved vascular function via restoration of blood vessel density. This uncertainty following a result in which aging is in some way turned back is exactly why more research is needed on this topic.

New insight into neovessel formation shows promise in future treatment of cardiovascular diseases

Bone morphogenetic proteins, BMPs, are growth factors originally discovered as regulators in bone formation. Later on, their regulatory role on the development and maintenance of a wide range of tissues has become apparent. BMPs have a vital role in the development of the cardiovascular system. In addition, BMPs have been shown to regulate blood vessel formation but their exact mechanisms are unknown. Crosstalk of BMP-signalling with a well-known blood vessel formation regulator, VEGF, and its downstream effectors is poorly understood.

The new study now shows that VEGF gene transfer or oxygen deprivation of the tissue induce the expression of BMPs. Bone morphogenetic factor 6 (BMP6) ligand was further demonstrated, for the first time, to regulate blood vessel formation. BMP6 was shown to act in endothelial cells via VEGFR2 and Hippo signalling pathways by inducing nuclear localization of Hippo signalling pathway mediator TAZ. The findings from this research improve our understanding of multifactorial communication of cell signalling pathways in blood vessel formation. The discoveries related to BMP6 and Hippo signalling can be used in the development of novel treatments for cardiovascular diseases.

BMP6/TAZ-Hippo signaling modulates angiogenesis and endothelial cell response to VEGF

BMP family members are important regulators of both vascular homeostasis and angiogenesis. Synergistic effect of VEGF and BMPs on vasculature have been previously detected in bone formation but their role in angiogenesis, particularly crosstalk with VEGFR2 signaling has remained elusive. Our data demonstrate that BMPs are widely expressed in endothelium of various tissues in hypoxia or normoxia and after VEGF-induced angiogenesis, and that BMP2 and BMP6 regulate VEGFR and Notch signaling. BMP6 was further demonstrated to induce neovessel formation in vivo. This is the first comprehensive data on BMPs in hypoxia, and in angiogenesis in various animal models.

OneSkin Launches a Topical Senolytic Treatment

Senescent cells are damaging to tissue function and health when they linger and grow in number, as becomes the case with age. They contribute to the chronic inflammation of aging via their signaling, the senescence-associated secretory phenotype. In skin, senescent cells are most likely responsible for a sizable fraction of the more problematic later life skin aging, in the 50s and on. It is less clear and less likely that they have much do to with the changes seen from the late 20s into the 40s.

The primary advantage inherent in targeting the mechanisms of aging specifically in skin is that the regulatory path to market for cosmetic treatments is much, much shorter than the alternative Investigational New Drug option. Thus OneSkin is making available a topical senolytic treatment that selectively destroys senescent cells in skin, and is doing so years in advance of FDA approval of any of the programs aiming to destroy senescent cells throughout the body. (That said, the senolytic treatment of dasatinib and quercetin, shown to destroy senescent cells in humans in a clinical trial, and capable of producing significant reversal of aging and age-related disease in mice, is very much available to any sufficiently motivated individual).

It would be interesting to see concrete data on the size of the effect produced by the OneSkin treatment, but that data isn’t available yet. Is this approach definitively better than the suppression of skin senescence achieved via long term topical use of rapamycin, for example? One would hope so, but we’ll have to wait and see. This lack of published, detailed data on effects in humans at the time of product launch is fairly characteristic of the supplement and cosmetics industries, and it makes it hard for the public at large to tell the difference between groups that are earnest and addressing a useful mechanism versus those that are not.

OneSkin launches topical senetherapeutic skin treatment

OneSkin is a longevity company on a mission to transform the way we think about skin. Today the company is launching OneSkin, a topical supplement containing a proprietary peptide, OS-01. Designed to reduce skin’s biological age, OneSkin claims to improve the skin barrier, support DNA damage repair and prevent the accumulation of senescent cells. OneSkin launched in 2016 as a biotech startup after acceptance into IndieBio, one of the world’s leading science accelerators.

“Our goal was to develop a product that extends skinspan, the period of time your skin is healthy and youthful. Our roots are in longevity science and we saw a need to shift the current paradigm. Instead of short-term fixes that focus purely on aesthetics, we’re targeting the root cause of aging and optimizing skin health on a molecular level. We believe what we put on our skin should be safe, effective, and help to maximize our human potential.”

OneSkin operates end-to-end research and development in-house with a team of experts in stem cell biology, skin regeneration, tissue engineering, biochemistry, bioinformatics, molecular biology, immunology, and aging. They measure skinspan in with MolClock – OneSkin’s first skin-specific molecular clock – and with skin aging modelling, using a proprietary technology and lab process which includes growing 3D human skin weekly and measuring how various products and ingredients influence gene expression of the many genes associated with aging and longevity.

“As we age, senescent cells begin to accumulate in our skin tissues. The accumulation of these cells can contribute to an increased presence of wrinkles, susceptibility to skin cancer, and a damaged skin barrier. Beyond its impact on skin, when left to linger, senescent cells send pro-inflammatory signals to the rest of the body, increasing the risk of age-related
diseases.” Preventing the accumulation of senescent cells reduces skin’s biological age as measured via MolClock, as well as leading to increased epidermal thickness, improved skin structure through increased collagen production and hyaluronic acid expression, maintained skin homeostasis and cell vitality.

The Challenge of Achieving Healthy Human Longevity

The big sea change of the past 10 to 15 years in aging research is that the scientific community is now near entirely behind the idea that aging is a viable target for therapy, and that we should be working towards greater healthy human longevity. Prior to this time, aging was near entirely a “look but don’t touch” field, in which any talk of medical intervention in aging was strongly discouraged. Making this change come about was a battle of years of patient advocacy (such as by the SENS Research Foundation and Methuselah Foundation), argument, and incremental advances in the science funded by small sums of hard-to-find research funding. It is perhaps hard for people today to recall how opposed the culture was to the idea of extending healthy life spans.

The present challenge is different: to ensure that the now willing workers and funding institutions direct their attention towards projects that will make a meaningful difference. Near all present work on intervention in the aging process is intended to do no more than modestly slow aging, tinkering with metabolism to slightly slow the accumulation of cell and tissue damage, or slightly blunt the consequences of damage. But the research community can do far better than this; it is possible to repair the damage that causes aging in order to produce rejuvenation. That strategy should be the primary focus on the research and development community, and it is not.

The initiative mentioned here, the Health Longevity Global Competition, is an example of this problem. If one digs in to see what exactly it is that they are supporting, one sees that it near all consists of projects that will clearly make no meaningful difference to the healthy human life span. It is not enough to have the enthusiasm and support of the research community. The strategy must also be correct.

Achieving healthy human longevity: A global grand challenge

Over the past century, major advances in medicine, public health, and socioeconomic development have led to unprecedented extensions of life expectancy worldwide. Global population aging presents both new opportunities and challenges. The COVID-19 pandemic has challenged recent advances in science and medicine and underscored the vulnerability of older populations to emerging diseases, alongside existing age-associated susceptibilities to noncommunicable diseases. Without innovation and adaptation, societal aging is poised to strain health care systems, economies, and social structures worldwide.

Yet, these and other looming stressors are not inevitable and could be mitigated, if not avoided, by accelerating biomedical and technological advancements, as well as socioeconomic infrastructures and policies to keep people healthier throughout their lives. By extending the health span, defined as the healthy years of life, societies can benefit from the tremendous social and economic opportunities that come with an active and vibrant older population. Numerous studies have identified common cellular and molecular mechanisms underlying the aging process, demonstrating that biological aging is modifiable and in some organisms health span or life span can even be extended. Many of the genetic pathways underlying aging and age-related disease – such as the insulin/IGF-1 and mammalian target of rapamycin (mTOR) pathways – play a critical role in maintaining homeostasis in response to environmental modulators such as injury, infection, stress, or food availability.

Other emerging areas of aging research include cellular senescence and senolytic therapy, regenerative medicine, immunoengineering, and genome editing and silencing. Therapies targeting these mechanisms and biological changes associated with aging are now being investigated in clinical trials (1). For example, senolytic compounds that selectively eliminate senescent cells are being studied in human clinical trials for osteoarthritis, glaucoma, and pulmonary fibrosis (2). Likewise, researchers are studying the effects of caloric restriction (3); metformin, a first-line drug for the treatment of type 2 diabetes (4); and rapamycin, an approved drug that inhibits mTOR, on the biology of human aging.

A fundamental question that remains is how interventions that show promise in improving life span or health span in model organisms will be evaluated in humans, where a complex interplay of factors underlies the aging process. Indeed, biological age often differs from chronological age. Some older individuals are less likely to develop age-related diseases than their age would predict, whereas some younger individuals prematurely develop age-related conditions. Thus, scientists have searched for biomarkers or other biological changes associated with aging and age-related declines that might act as “aging clocks.”

Despite recent progress, the current research and innovation ecosystem is not poised to deliver the transformative innovations needed to achieve healthy longevity. To achieve major breakthroughs, we need to reexamine our fundamental approach to aging research and innovation. The traditional biomedical research funding model continues to be largely risk averse. Typically, incremental and clearly feasible research is funded, whereas bold, high-risk but high-gain proposals are often less well supported. Similarly, we see a rather conservative approach to drug discovery, which is designed to target, manage, or cure one disease at a time.

For these reasons, the National Academy of Medicine (NAM) has launched the Healthy Longevity Global Competition to catalyze breakthrough research and generate transformative and scalable innovations by mobilizing action across disciplines and sectors – from basic research to technology, care delivery, financing, community development, and social policy. An important goal of this Global Competition is to stimulate worldwide interest from scientists and innovators, thereby creating a global movement to dramatically increase innovation and groundbreaking advances in aging research. In October 2019, NAM and global collaborators launched the Global Competition with the participation of 49 countries and territories. During the first phase of the competition over 3 years, more than 450 Catalyst Awards will be distributed globally, representing over 30 million in seed funding to attract bold, audacious research ideas. In the second phase, “Accelerator Awards” will provide additional substantial funding or support for projects that have demonstrated proof of concept with potential for commercialization. In the third and final phase, one or more Grand Prizes totaling over 4 million will reward breakthrough achievements with the promise of global impact.

Targeting NAD+ Metabolism for the Treatment of Cardiovascular Disease

Nicotinamide adenine dinucleotide (NAD+) is important to mitochondrial function, the supply of chemical energy store molecules to power cellular processes, and thus to cell and tissue function. Levels of NAD+ decline with age, a part of the deterioration of mitochondrial function throughout the body:. Too little NAD+ is created, too little NAD+ is recycled after use. This downturn occurs for reasons in which the proximate causes are fairly clear, meaning which of the other molecules required for NAD+ synthesis and recycling come to be in short supply in old tissues, but a map of the deeper connections to the known root causes of aging is lacking.

Various vitamin B3 derived supplements have been shown to increase NAD+ levels in older individuals. Those that have undergone clinical trials were no better in this regard than the effects of structured exercise programs. It seems plausible that this performance can be improved upon, but will that produce better effects than exercise? That remains to be determined. As noted in this open access paper, there are plenty of age-related conditions in which loss of mitochondrial function is important, and either exercise or pharmacological approaches to produce NAD+ upregulation may produce benefits in older individuals by reducing this loss of function.

Nicotinamide adenine dinucleotide or NAD+, is one of the most essential small molecules in mammalian cells. NAD+ interacts with over 500 enzymes and plays important roles in almost every vital aspect in cell biology and human physiology. Dysregulation of NAD+ homeostasis is associated with a number of diseases including cardiovascular diseases (CVD). Particularly, modulation of NAD+ metabolism has been proposed to provide beneficial effects for CVD settings that are highly associated with sudden cardiac death (SCD), such as ischemia/reperfusion injury (I/R injury), heart failure, and arrhythmia.

The heart, along with the kidney and the liver has the highest level of NAD+ among all the organs. In mammalian cells, NAD+ is synthesized via two distinct pathways: the de novo pathway and the salvage pathway. The de novo pathway generates NAD+ from tryptophan through the kynurenine metabolic pathway, or nicotinic acid (NA) through the Preiss-Handler pathway. Nevertheless, most organs other than the liver, including the heart, use the salvage pathway as the main route to generate NAD+. Metabolic profiling of NAD+ biosynthetic routes in mouse tissues was established by measuring the in vitro activity of enzymes, the levels of substrates and products, and revealed that 99.3% of NAD+ in the heart is generated by the salvage pathway. On the other hand, enzymes involved in the de novo pathway are of low expression and low activity in the heart. The salvage pathway generates NAD+ from the NAD+ degradation product nicotinamide (NAM). NAM is converted into an intermediate product nicotinamide mononucleotide (NMN) via NAM phosphoribosyltransferase (NAMPT) – the rate limiting enzyme in the salvage pathway.

Both reductions in NAD+ biosynthesis and activation of NAD+-consuming enzymes can cause NAD+ depletion, which in turn may lead to dysregulation of numerous vital cellular functions. Chronic dysregulation of NAD+-dependent cell functions ultimately results in the development of CVD. An increasing number of studies, particularly in rodent models, have shown that boosting NAD+ is beneficial for CVD. Elevation of NAD+ levels can be achieved by supplementing NAD+, NAD+ precursors or modulating activities of enzymes responsible for NAD+ generation or degradation such as NAMPT, PARP, and CD38.

Human studies have shown that NAD+-boosting therapy can reduce mortality and provide moderate clinical benefits for patients with CAD. However, conflicting results on critical clinical outcomes such as incidence of composite mortality and major vascular events have raised the concern that whether NAD+-boosting therapy can ultimately become a primary treatment for CAD and other CVD. Several important aspects may help overcome these hurdles. First, it is critical to determine the effective dose of NAD+ boosters for each individual patient. Direct measurement for NAD+ level or NAD+ metabolome from accessible samples such as plasma should be considered. Second, the optimal time window for NAD+ booster supplementation remains to be established in human subjects. NAD+-boosting therapy should coordinate with the intrinsic circadian oscillation of NAD+ level in human body so that maximal beneficial effects can be achieved. With a more nuanced understanding of NAD+ biology in the heart and clinical studies designed with more sophistication, we anticipate that NAD+-boosting therapy would ultimately harness its potential for SCD-associated CVD.

Molecules Leaking from Damaged Muscle Fibers can Activate Muscle Stem Cells

Declining muscle stem cell function appears likely to be the most important contributing cause of sarcopenia, the characteristic loss of muscle mass and strength with age. Studies of the stem populations that support muscle tissue have suggested that the cells are largely intact and capable, but quiescent. This may be a reaction to changes in signaling resulting from the age-damaged and inflammatory tissue environment, or it may be due to damage and dysfunction in the cells making up the stem cell niche, or both. Beyond the few efforts directed at repairing the underlying damage that causes these issues, such as accumulation of senescent cells, there is some interest in uncovering signals that will force muscle cells to get back to work. The research here is an example of this sort of initiative.

Skeletal muscle is made up of bundles of contracting muscle fibers and each muscle fiber is surrounded by satellite cells – muscle stem cells that can produce new muscle fibers. Thanks to the work of these satellite cells, muscle fibers can be regenerated even after being bruised or torn during intense exercise. Satellite cells also play essential roles in muscle growth during developmental stages and muscle hypertrophy during strength training. However, in refractory muscle diseases like muscular dystrophy and age-related muscular fragility (sarcopenia), the number and function of satellite cells decreases. It is therefore important to understand the regulatory mechanism of satellite cells in muscle regeneration therapy.

Since satellite cells are activated when muscle fibers are damaged, researchers hypothesized that muscle damage itself could trigger activation. However, this is difficult to prove in animal models of muscle injury so they constructed a cell culture model in which single muscle fibers, isolated from mouse muscle tissue, were physically damaged and destroyed. Using this injury model, they found that components leaking from the injured muscle fibers activated satellite cells, and the activated cells entered the G1 preparatory phase of cell division. Further, the activated cells returned to a dormant state when the damaged components were removed, thereby suggesting that the damaged components act as the activation switch.

The research team named the leaking components “Damaged myofiber-derived factors” (DMDFs), after the broken muscle fibers, and identified them using mass spectrometry. Most of the identified proteins were metabolic enzymes, including glycolytic enzymes such as GAPDH, and muscle deviation enzymes that are used as biomarkers for muscle disorders and diseases. GAPDH is known as a “moonlighting protein” that has other roles in addition to its original function in glycolysis, such as cell death control and immune response mediation. The researchers therefore analyzed the effects of DMDFs, including GAPDH, on satellite cell activation and confirmed that exposure resulted in their entry into the G1 phase. Furthermore, the researchers injected GAPDH into mouse skeletal muscle and observed accelerated satellite cell proliferation after subsequent drug-induced muscle damage. These results suggest that DMDFs have the ability to activate dormant satellite cells and induce rapid muscle regeneration after injury.

Phosphate as an Agent of Accelerated Aging

Here find an interesting viewpoint on the role of phosphate in mammalian biochemistry, suggesting that it tilts the playing field in the direction of faster degenerative aging. This emerges from work on the longevity-associated gene klotho and its effects on kidney function and vascular function in aging. As is usually the case in such matters, there is no great debate over whether or not specific mechanisms and contributions to aging and age-related diseases exist. The question is whether or not the size of the effect is large enough to care about, and that is always much harder to answer, given the immense complexity of cellular biochemistry.

During the evolution of skeletons, terrestrial vertebrates acquired strong bones made of calcium-phosphate. By keeping the extracellular fluid in a supersaturated condition regarding calcium and phosphate ions, they created the bone when and where they wanted simply by providing a cue for precipitation. To secure this strategy, they acquired a novel endocrine system to strictly control the extracellular phosphate concentration. In response to phosphate intake, fibroblast growth factor-23 (FGF23) is secreted from the bone and acts on the kidney through binding to its receptor Klotho to increase urinary phosphate excretion, thereby maintaining phosphate homeostasis.

The FGF23-Klotho endocrine system, when disrupted in mice, results in hyperphosphatemia and vascular calcification. Besides, mice lacking Klotho or FGF23 suffer from complex aging-like phenotypes, which are alleviated by placing them on a low-phosphate diet, indicating that phosphate is primarily responsible for the accelerated aging. Phosphate acquires the ability to induce cell damage and inflammation when precipitated with calcium. In the blood, calcium-phosphate crystals are adsorbed by serum protein fetuin-A and prevented from growing into large precipitates. Consequently, nanoparticles that comprised calcium-phosphate crystals and fetuin-A, termed calciprotein particles (CPPs), are generated and dispersed as colloids.

CPPs increase in the blood with an increase in serum phosphate and age. Circulating CPP levels correlate positively with vascular stiffness and chronic non-infectious inflammation, raising the possibility that CPPs may be an endogenous pro-aging factor. Terrestrial vertebrates with the bone made of calcium-phosphate may be destined to age due to calcium-phosphate in the blood.

Myokines Mediate the Effects of Exercise on Health

Mapping mammalian biochemistry is a sizable task, and much of that biochemistry remains poorly understood and categorized. Cell signaling is a vast topic in and of itself. Here researchers discuss myokines, signal molecules generated by muscle cells as a result of exercise. These diverse signals are influential on tissue function and health, and mediate some fraction of the benefits resulting from physical activity. Further, some clearly change in abundance with age, and might therefore be useful targets for interventions intended to better maintain health and function with aging.

In recent decades, it has been discovered that contracting skeletal muscles release various hormone-like substances. These activators are called myokines, which are small proteins and proteoglycan peptides that are produced and secreted by skeletal muscle cells in response to muscle contractions. Various myokines secreted by skeletal muscles during aerobic and anaerobic exercises have been studied in connection with various human diseases. For a long time, skeletal muscles were only recognized as being involved in the physical aspects of exercise. However, with the discovery of exercise-induced myokines, skeletal muscles have been demonstrated to be involved in the maintenance of metabolic homeostasis. Although the detailed mechanisms are not clear, both skeletal muscle contraction and mass maintenance appear to be actively involved in maintaining health and preventing disease development in the elderly, particularly considering the rapid deterioration of muscle physiology with aging.

This review summarizes 13 myokines regulated by physical activity that are affected by aging and aims to understand their potential roles in metabolic diseases. We categorized myokines into two groups based on regulation by aerobic and anaerobic exercise. With aging, the secretion of apelin, β-aminoisobutyric acid (BAIBA), bone morphogenetic protein 7 (BMP-7), decorin, insulin-like growth factor 1 (IGF-1), interleukin-15 (IL-15), irisin, stromal cell-derived factor 1 (SDF-1), sestrin, secreted protein acidic rich in cysteine (SPARC), and vascular endothelial growth factor A (VEGF-A) decreased, while that of IL-6 and myostatin increased. Aerobic exercise upregulates apelin, BAIBA, IL-15, IL-6, irisin, SDF-1, sestrin, SPARC, and VEGF-A expression, while anaerobic exercise upregulates BMP-7, decorin, IGF-1, IL-15, IL-6, irisin, and VEGF-A expression. Myostatin is downregulated by both aerobic and anaerobic exercise.

Although the 13 myokines reviewed are all stimulated by exercise, each has unique characteristics. In brief, apelin is an anti-aging factor and has positive effects on hypertension and ischemia-reperfusion injury when combined with exercise. BAIBA prevents metabolic diseases by acting as an osteocyte survival factor, protecting against mitochondrial breakdown, and attenuating bone and skeletal muscle loss. BMP-7 is an important factor in bone formation and skeletal muscle mass maintenance. Decorin, IGF-1, and SDF-1 have positive effects on tendon strength, bone and tissue development, and skeletal muscle regeneration, respectively. IL-15 facilitates fibroblast collagen synthesis and cell proliferation. IL-6 contributes to the maintenance of glucose homeostasis, obesity regulation, microglial function, and lactate production. Irisin might become a treatment for Alzheimer’s disease because of its positive influence on neuron functional impairment. The most interesting is myostatin. Unlike the other myokines, exercise reduces its secretion. It is beneficial in chronic heart failure, chronic kidney disease, and lipidomic abnormalities. Sestrin helps prevent the development of age-associated metabolic diseases and sarcopenia. SPARC, which is increased by aerobic exercise, has potential as a cancer treatment. VEGF-A, which is upregulated by both anaerobic and aerobic exercise, is involved in the growth and survival of skeletal muscle.

The biggest takeaway of our review is that both aerobic and anaerobic exercises exert positive effects on skeletal muscles by releasing various myokines that are beneficial to the elderly. Given that most studies on long term physical activity in the elderly have focused on aerobic exercises, it is worth broadening the scope of research by examining the need for anaerobic exercise.

Chromatin Changes in the Aging of Stem Cells

Chromatin is the name given to the packed structure of nuclear DNA and surrounding molecules, tightly coiled in the center of the cell. Chromatin structure and the molecules responsible for regulating that structure are a part of the complex epigenetic systems that determine the pace of protein production, and thus cell behavior. Chromatin changes in characteristic ways with age, a situation that is far from fully mapped and understood, but is particularly important in stem cell aging. Stem cell populations become less active with age, most likely an evolved response to rising levels of tissue damage that acts to limit the incidence of cancer. The cost of that protection is a slow decline into organ failure, disease, and death. Safely restoring youthful function in the scores of different stem cell populations throughout the body is an important goal for the future of medicine.

In most tissues, adult stem cells occupy a rare but powerful functional compartment, capable of differentiating into multiple tissue-specific lineages. Some stem cell types can remain quiescent until environmental signals prompt them to divide whereas other types continuously divide to repopulate lost or injured tissue. This process is critical and is harnessed during injury and disease to enhance tissue repair. Stem cells in adult tissues show dramatic reductions in regenerative capacity with age. Stem cells undergo replicative aging (due to repeat proliferative cycles), chronological aging (due to chronic changes during prolonged quiescent state) and even show senescence or exhaustion phenotypes. Prolonged quiescence can accumulate DNA damage and cause chronological aging due to additive insults and error-prone damage repair mechanisms.

In response to replication signals, stem cells are activated to divide. Two major aspects of stem cell division are self-renewal and differentiation. Studies across multiple organisms and stem cell types have revealed distinct effects of aging on self-renewal capacity and differentiation potential depending on stem cell type. This is manifested in either loss or gain of stem cell numbers, delay in activation kinetics, altered fate, lineage bias and/or compromised function of differentiated cells with age. Ultimately, these changes in aged stem cells eventually lead to physiological disorders and age-dependent pathologies in the organism.

Evidence suggests a reconfiguration of the chromatin state to a global increase in DNA hypermethylation, an imbalanced heterochromatin, a loss of active enhancers, even a disruption of chromosome territories. The consequences of these epigenomic changes are reflected in functional outcomes such as altered self-renewal patterns and/or senescence phenotypes that impact stem cell number. Additionally, there is dramatic change in stem cell potential, lineage bias, delayed activation kinetics and ultimately higher frequencies of disease phenotypes such as cancer.

While “drift” patterns are not necessarily programmed, it may be possible to delay their accumulation or even reverse the changes by late-life epigenetic drug interventions or cellular epigenome reprogramming strategies that “wipe out and start over”. Complete reprogramming of aged hematopoietic stem cells (HSCs) into induced pluripotent stem cells – by overexpression of OCT4, SOX2, KLF4, and MYC (OSKM) – followed by blastocyst complementation, re-differentiation into HSCs, and serial transplantation showed remarkable repopulation capacity invariant with young cells. Since the genetic material of the stem cells was unchanged, this type of rejuvenation was attributed to an epigenetic resetting although the exact mechanisms remain to be identified. Partial reprogramming by short-term cyclic expression of OSKM also had positive outcomes in aged mice. There is also evidence from other studies that partial reprogramming can turn back the DNA methylation clock further supporting the notion that reprogramming directly affects the epigenome. However, whether similar changes occur in stem cells remains to be investigated.

miR-195 Promotes Blood-Brain Barrier Integrity by Suppressing TSP1 Activity

The blood-brain barrier consists of specialized cells that line central nervous system blood vessels, allowing only certain cells and molecules to pass to and from the brain. This barrier becomes leaky with age, and this results in growing inflammation and dysfunction in the brain. Inappropriate molecules find their way through and provoke the immune system of the brain into a damaging, lasting inflammatory reaction. This is an important early stage in the progression towards neurodegeneration and consequent cognitive decline. Researchers here report on their investigations of the biochemistry of blood-brain barrier dysfunction, focusing on TSP1 and its ability to disrupt the blood-brain barrier by breaking down proteins involved in the tight junction structures that link cells together. MicroRNA-195 can block some of this disruption when delivered intravenously, which makes it a potentially interesting basis for treatment.

Blood-brain barrier (BBB) disruption contributes to neurodegenerative diseases. Loss of tight junction (TJ) proteins in cerebral endothelial cells (ECs) is a leading cause of BBB breakdown. We recently reported that miR-195 provides vasoprotection, which urges us to explore the role of miR-195 in BBB integrity. Here, we found cerebral miR-195 levels decreased with age, and BBB leakage was significantly increased in miR-195 knockout mice. Furthermore, exosomes from miR-195-enriched astrocytes increased endothelial TJ proteins and improved BBB integrity.

To decipher how miR-195 promoted BBB integrity, we first demonstrated that TJ proteins were metabolized via autophagic-lysosomal pathway and the autophagic adaptor p62 was necessary to promote TJ protein degradation in cerebral ECs. Next, proteomic analysis of exosomes revealed miR-195-suppressed thrombospondin-1 (TSP1) as a major contributor to BBB disruption. Moreover, TSP1 was demonstrated to activate selective autophagy of TJ proteins by increasing the formation of claudin-5-p62 and ZO1-p62 complexes in cerebral ECs while TSP1 impaired general autophagy.

Delivering TSP1 antibody into the circulation showed dose-dependent reduction of BBB leakage by 20%-40% in 25-month-old mice. Intravenous or intracerebroventricular injection of miR-195 rescued TSP1-induced BBB leakage. Dementia patients with BBB damage had higher levels of serum TSP1 compared to those without BBB damage, while the normal subjects had the lowest TSP1. Taken together, the study implies that TSP1-regulated selective autophagy facilitates the degradation of TJ proteins and weakens BBB integrity. An adequate level of miR-195 can suppress the autophagy-lysosome pathway via a reduction of TSP1, which may be important for maintaining BBB function.

COVID-19 Is Only One of the Compelling Arguments for Developing the Means of Immune System Rejuvenation

Infectious disease is a far greater risk for the old than for the young. But then so is cancer. Both are conditions driven by the age-related failure of immune system competence, a growing inability to respond to vaccines and to destroy pathogens and errant cells, a state known as immunosenescence. Further, the failing immune system becomes inappropriately overactive at the same time as losing its efficacy, generating chronic inflammation that disrupts normal tissue function and spurs the development of numerous age-related diseases. Restoring a youthful immune function would be enormously beneficial and greatly reduce mortality and age-related disease across the board in older people. While this is a topic of interest in the research community, nowhere near enough resources are directed to achieving this goal, given the enormous cost and suffering that results from immune aging.

Unlike fine wine, the human body does not improve with age. Hearing fades, skin sags, joints give out. Even the body’s immune system loses some of its vigour. This phenomenon, known as immunosenescence, might explain why older age groups are so hard-hit by COVID-19. And there is another troubling implication: vaccines, which incite the immune system to fight off invaders, often perform poorly in older people. The best strategy for quelling the pandemic might fail in exactly the group that needs it most.

The human immune system is mind-bendingly complex, and ageing affects nearly every component. Some types of immune cell become depleted: for example, older adults have fewer naive T cells that respond to new invaders, and fewer B cells, which produce antibodies that latch on to invading pathogens and target them for destruction. Older people also tend to experience chronic, low-grade inflammation, a phenomenon known as inflammageing. Although some inflammation is a key part of a healthy immune response, this constant buzz of internal activation makes the immune system less responsive to external insults. The upshot is a poorer reaction to infections and a dulled response to vaccines, which work by priming the immune system to fight off a pathogen without actually causing disease.

Many of the immune changes that come with ageing lead to the same result: inflammation. So researchers are looking at drugs that will calm this symptom. A class of drug, called senolytics, helps to purge the body of cells that have stopped dividing but won’t die. These senescent cells are typically cleared by the immune system, but as the body ages, they begin to accumulate, ramping up inflammation. In August, a team launched a 70-person trial to test whether a senolytic called fisetin can curb progression of COVID-19 in adults aged 60 or older. They also plan to test whether fisetin can prevent COVID-19 infection in nursing-home residents.

In general, developing medications to improve immune function seems like a much smarter strategy than creating vaccines specifically for elderly people. Individual vaccines target specific pathogens, but an immune-boosting medication could be used with any vaccine. “I think the net result of all this will be renewed interest in understanding the defect in the immune response in the elderly. COVID-19 has brought to the front something that a lot of people have ignored.”

Obese Individuals Have an Impaired Synaptic Plasticity Response

Researchers here provide initial evidence for obesity to impair synaptic plasticity, albeit a fairly indirect assessment of plasticity in just one area of the brain. Excessive visceral fat tissue is metabolically active and contributes to chronic inflammation, capable of impairing tissue function throughout the body. Being overweight or obese correlates very robustly with the risk of suffering many common conditions, and arguably accelerates the aging process via an increased pace of production of senescent cells.

Obesity is characterised by excessive body fat and is associated with several detrimental health conditions, including cardiovascular disease and diabetes. There is some evidence that people who are obese have structural and functional brain alterations and cognitive deficits. It may be that these neurophysiological and behavioural consequences are underpinned by altered plasticity. This study investigated the relationship between obesity and plasticity of the motor cortex in people who were considered obese (n = 14, nine males, aged 35.4 ± 14.3 years) or healthy weight (n = 16, seven males, aged 26.3 ± 8.5 years).

A brain stimulation protocol known as continuous theta burst transcranial magnetic stimulation was applied to the motor cortex to induce a brief suppression of cortical excitability. The suppression of cortical excitability was quantified using single-pulse transcranial magnetic stimulation to record and measure the amplitude of the motor evoked potential in a peripheral hand muscle. Therefore, the magnitude of suppression of the motor evoked potential by continuous theta burst stimulation was used as a measure of the capacity for plasticity of the motor cortex.

Our results demonstrate that the healthy-weight group had a significant suppression of cortical excitability following continuous theta burst stimulation (cTBS), but there was no change in excitability for the obese group. Comparing the response to cTBS between groups demonstrated that there was an impaired plasticity response for the obese group when compared to the healthy-weight group. This might suggest that the capacity for plasticity is reduced in people who are obese. Given the importance of plasticity for human behaviour, our results add further emphasis to the potentially detrimental health effects of obesity.

Cerebrovascular Disease Prevention as a Priority in Dementia Prevention

Disruption of the blood flow to the brain, either a slow decline in supply due to vascular aging, or following a stroke, is an important contributing factor in the development of dementia. The brain requires a great deal of energy to function, and thus the supply of nutrients and oxygen is even more critical than is the case for other organs. Reductions in that supply have consequences.

Cerebrovascular diseases include a variety of medical conditions that affect the blood vessels of the brain and the cerebral circulation. These include conditions that may cause acute interruption of cerebral circulation and subsequent acute neuronal damage, such as ischaemic or haemorrhagic stroke, and disorders that may cause chronic pathological changes in small vessels and neurological dysfunction, such as cerebral small vessel diseases. Patients with cerebrovascular diseases, both acute and chronic, usually have multidimensional functional impairments to the brain and an increased risk of cognitive impairment and dementia.

Despite cognitive impairment after cerebral small vessel disease being a common cause of impairment of brain function, its underlying pathogenesis and mechanism are poorly understood. Recent studies showed that early impairment of cognition may be induced by disruption of the glio-neuro-vascular unit. Small vessel pathologies due to vascular risk factors may induce breakdown in the integrity of the blood-brain barrier and cerebral blood flow deficits. Although not yet tested in prospective longitudinal studies, structural and functional alterations of cerebral small vessels may trigger the cascade of molecular signals (for example, activation of innate immunity, vascular oxidative stress, and inflammation), leading to disruption of the glio-neuro-vascular unit. Neurovascular dysfunction alters the homeostasis of the brain microenvironment and promotes accumulation of amyloid and tau protein in regions involved in cognition, leading to early vascular and neurodegenerative cognitive impairment.

As cerebrovascular diseases and dementia are so closely interlinked, amelioration of vascular risk and vascular damage offers a new dawn for preventing not only vascular dementia but also mixed and even Alzheimer’s dementias, and it may even offer alternative routes to clear amyloid and tau protein aggregation. For example, a substudy of the SPRINT MIND (Systolic Blood Pressure Intervention Trial Memory and Cognition in Decreased Hypertension) trial showed that intensive blood pressure reduction decreased progression of white matter hyperintensities, mild cognitive impairment, and probable dementia. The results of these trials indicated that patients with cerebrovascular disease or vascular risk factors might be a potential target population to prevent dementia.

ELOVL2 in the Aging of the Eye

The development of epigenetic clocks for the assessment of biological age is a popular area of study, but connecting characteristic age-related epigenetic changes at specific CpG sites on the genome to specific underlying mechanisms of aging is slow going at best. There are many such sites and only so many scientists and only so much funding. An example of this sort of work is presented here, illustrative of the complexity involved in this area of research. The gene ELOVL2 is associated with a few sites that are strongly linked to age. There is a lot to say about potentially relevant mechanisms, and a great many gaps left to be filled in, even when just focused down on a single small part of the body, the retina in this case.

Epigenetic aging of tissues and organs has been tightly correlated with global genome DNA methylation changes in specific regions, called CpG islands. A number of recent studies have shown that CpG methylation (CpGme) patterns progressively change during aging in a variety of tissues and cells such as blood, muscle, brain, lung, and colon. One major question is whether these methylation changes merely correlate with aging, or if there any functional role of these epigenetic changes in regulating aging. Interestingly, within the top ten markers predictive of human epigenetic age, four are localized in the CpG islands in the regulatory element of the ELOVL2 gene, accounting for over 70% of the one “methylation clock” model. Consequently, methylation of the ELOVL2 regulatory region has been shown in many studies to correlate strongly with the biological age of individuals, as well as in rodents.

ELOVL2 is an enzyme that elongates long-chain omega-3 and omega-6 polyunsaturated fatty acids (LC-PUFAs), precursors of docosahexaenoic acid (DHA) and very-long-chain PUFAs (VLC-PUFAs), playing important role in retina biology. The fatty acids composition in the retina is unique – the retina is particularly enriched in PUFAs, with DHA constitutes 40-50% of the total fatty acids in the photoreceptor outer disc membranes. PUFAs are well known to play important roles in the retina and deficiency of LC-PUFAs has been shown to be associated with increased risk of the dry form of age-related macular degeneration (AMD), a highly prevalent retinal disease. Recent studies suggest that individuals who self-reported intake of foods rich in omega 3 PUFAs were 30% less likely to develop central geographic atrophy (GA) and 50% less likely to develop AMD than subjects with the lowest self-reported intake.

While methylation of the ELOVL2 promoter is highly correlated with chronological age, whether ELOVL2 protein has a functional role in aging has not been investigated. We observed an age-dependent increase in Elovl2 regulatory region methylation associated with concomitant downregulation of Elovl2 expression on mRNA and protein levels. Next we observed Elovl2 expression in cone and rod photoreceptors, as well as the retinal pigment epithelium. We also observed a significant age-related decline of the expression of the Elovl2 in the eye. The same age-dependent changes of Elovl2 methylation and gene expression were observed in the mouse liver, indicating that age-associated methylation of Elovl2 occurs in multiple tissues in the mouse, similarly to what was observed previously in humans.

Next, we investigated the function of Elovl2 in aging in vivo. As Elovl2 heterozygous mice are infertile, we created a knock-in point mutation using Crispr-Cas9 technology, Elovl2-C234W. Inhibiting Elovl2 accelerates aging in the mouse retina. Using lipidomics, we confirmed that Elovl2-C234W mutation results in loss of ELOVL2-specific function. We further investigated the effect of Elovl2-C234W mice on both anatomic and functional surrogates of aging in the mouse eye. These included autofluorescent (AF) deposits in the fundus, which increases with age, as well as the electroretinogram (ERG), which shows a decrease in the maximum scotopic response with age. In Elovl2-C234W mice, we noticed an increase in AF deposits as well as a decrease in ERG compared to age-matched controls, suggesting that inhibiting Elovl2 accelerates aging in the mouse retina.