Fight Aging! Newsletter, May 3rd 2021

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  • B Cell Depletion Reverses Measures of Alzheimer's Progression in Mouse Models
  • Lessons from 50 Years of the War on Cancer, Looking Ahead to the War on Aging
  • Cell Therapy to Enhance the Repair Response of the Brain
  • CDC42 Inhibition Promotes Intestinal Stem Cell Function in Aged Mice
  • In the Best of Plausible Futures, We Will All Be Occasional Cancer Patients
  • Inflammatory Macrophages are Involved in Aortic Aneurysm Formation
  • Retinal Cells that Can Integrate into Tissue and Survive Following Transplantation
  • Klotho Reverses Some Muscle Aging in Old Mice, but not in Very Old Mice
  • Towards a Non-Invasive Biomarker of Aging Based on Volatile Organic Compounds
  • Reviewing Myostatin in Muscle Growth, and Efforts to Produce Myostatin-Targeted Therapies
  • Sirtuin 6 in Mammalian Aging
  • A Small Human Study of Short Term Nicotinamide Mononucleotide Supplementation
  • Accelerating Progress Towards the Reversible Cryopreservation of Organs
  • Targeting Cellular Senescence in the Aging Vascular Endothelium
  • Bone Aging, Cellular Senescence, and Osteoporosis

B Cell Depletion Reverses Measures of Alzheimer's Progression in Mouse Models

In today's open access paper, researchers report results that suggest the contribution of B cells, a type of immune cell, to the progression of Alzheimer's disease is meaningful. Approaches to the selective destruction of the B cell complement in mice are fairly well developed, given that it is not harmful in the short term to live without B cells, and the B cell population regenerates quite rapidly when it is depleted. Applying such a method to clear B cells in Alzheimer's mouse models resulted in slowing of progression in the early stages and reversal in the later stages of the condition.

The mechanism of interest here is chronic inflammation in the brain, important to the progression of neurodegenerative conditions. Removing B cells from the picture in some way breaks some of the feedback loops involved in the growing levels of inflammation characteristic of aging and Alzheimer's disease. While the researchers speculate on the details, more work would have to be carried out to pin down exactly what is going on here. B cells are by no means as well studied in the context of Alzheimer's disease as are other types of immune cell, such as microglia.

One interesting point relates to the cells known as age-associated B cells. These age-associated B cells build up with age, as the name might suggest, and are known to be pathological. Trying to remove them has been the motivation for a number of studies of targeted B cell clearance, and removing them does indeed produce benefits in old animals. The researchers here believe that age-associated B cells are not involved in the B cell related contribution inflammation of Alzheimer's disease, however. It is some more general participation of B cells in the state of the aging brain.

Therapeutic B-cell depletion reverses progression of Alzheimer's disease

We provide counterintuitive evidence for a "dark" side of B cells - they exacerbate manifestation of Alzheimer's disease (AD)-like symptoms in addition to producing potentially beneficial amyloid-β plaque-reducing immunoglobulins and expressing AD-ameliorating cytokines. Although the exacerbation in Rag-deficient APP and 5×FAD mice is linked to the loss of protective B cells and T cells, our data revealed that the genetic loss of B cells alone or their transient depletion at the onset of AD improves the disease symptoms of three different mouse models.

Unlike a recent report that linked AD progression to the reduction of anti-inflammatory B1a cells in 5×FAD mice, the numbers of B1a and B1b cells in peripheral blood, spleen, and cervical lymph nodes were either unaffected (in 5×FAD mice even when followed for 4, 7, and 12 months) or upregulated (in 3×TgAD and APP/PS1 mice). However, regardless of their numbers, we recently reported that the function of B1a cells is not static and is rather controlled by the inflammatory milieu. In the aged hosts, B1a cells lose their anti-inflammatory activity and acquire pathogenic functions, such as becoming 4-1BBL+ B1a cells (termed 4BL cells) that induce cytolytic granzyme-B+ CD8+ T cells and promote insulin resistance. In concordance, B1 cells (as well B2 cells, in some models) in AD mice also appeared to acquire an inflamed phenotype, as they upregulated expression of cytokines. Although age-associated B cells also accumulate in aging, we did not detect their involvement in our three types of mice with AD.

Consistent with a recent RNA-seq report that revealed presence of mature B cells in the brains of AD mice, our data indicate that AD increases B cells in the brain, and their IgG in the cortex and hippocampus parenchyma, which was often colocalized with amyloid-β plaques and activated microglia. As in multiple sclerosis and cognitive dysfunction following stroke, B cells in the brain presumably produce immunoglobulins and proinflammatory factors exacerbating AD-promoting neuroinflammation. Our data also indicate that the loss of B cells, thus immunoglobulin G, in the brain significantly retards the development of AD. Although the mechanism of this process is a topic of a different study, we think that brain IgG (or its immune complex) alone or in concert with B-cell cytokines exacerbates neuroinflammation in AD.

Lessons from 50 Years of the War on Cancer, Looking Ahead to the War on Aging

Today I'll point out a high quality commentary on what we might take away from the War on Cancer, launched 50 years ago. In the longevity advocacy community, the notable past success in building a cancer research community, as well as in persuading the public to support large-scale efforts to bring an end to cancer, are viewed as an aspirational goal. Over the years there has been talk of attempting to reproduce these successes in order to engineer public support for a War on Aging. There were many moving parts to the War on Cancer: decades of preliminary patient advocacy and lobbying; the evolution of public attitudes towards cancer and cancer research; progress in science and funding; the challenges inherent in the growth of a truly massive research community; the creation of a funding ecosystem to power that broad range of research. Much might be learned from an examination of each.

There are other lessons we might learn here, however, such as the modes of failure that emerge from focusing on diseases of aging, such as cancer, rather than on aging itself. Or that the wrong approach to a problem can absorb any amount of funding to produce only incremental progress. Diseases of aging are caused by the mechanisms of aging, yet little to no work made the deliberate effort to target those mechanisms until comparatively recently. Attempting to treat the disease, rather than its cause, inevitably has limited utility. As the author points out here, the War on Cancer was set up in a way that limits the scope of benefits to health that can result. Prevention is a noble goal, but cancer cannot be entirely (or even largely) prevented by lifestyle choices, as one cannot choose not to age.

50 years of the "war on cancer": lessons for public health and geroscience

Reflecting on the realities of the past 50 years of the "war on cancer", and the reality of the prevalence of comorbidity for populations surviving to the upper limits of the human lifespan, we cannot continue on the same course originally plotted out by the National Cancer Act of 1971. Today cancer is still the second leading cause of death in America. The project of behaviour control has not successfully altered this outcome, in large part because it does not alter the most significant risk factor for cancer - age.

I am not suggesting that public health should concede the battle and abandon the important preventative measures of smoking cessation and a physically active lifestyle. Of course not. But we should have the humility to recognize that doubling down on these efforts for the next half a century is unlikely to yield a significant health dividend for today's ageing populations. Strategic innovation in preventative medicine will be required. The strategy of behaviour control must be supplemented with the strategy of rate control. In order to unify the aspirations to "save people" from cancer mortality while also ensuring they live longer and better lives, the inborn ageing process must also be targeted. To fixate on disease elimination without also aspiring to alter the rate of ageing will prove costly with diminishing health returns because it does not increase the healthspan.

The public health lessons of the 50-year campaign to defeat cancer in the USA ought to inform global public health more generally. The European Commission, for example, has recently identified cancer as a "mission area". A House of Lords "Science and Technology Select Committee" UK report was released, the catalyst of which an assessment of the feasibility of the government's Ageing Society Grand Challenge mission. Chapter 6 of this report is entitled "The Ageing Society Grand Challenge", and it sets the goal of increasing healthy life expectancy by 5 years by 2035. The World Health Organization dedicated the decade 2021-2030 as the decade of "healthy ageing". The campaign identifies four main areas of action-age-friendly environments, combating ageism, integrated care and long-term care. These are all morally laudable, but incomplete, prescriptions.

Like the EU report on defeating cancer, what is missing from the World Health Organization's action plan is undertaking the committed action to develop an applied gerontological intervention to increase the human healthspan. Geroscience is an integral element of public health for today's ageing populations. Redressing the imbalance between the research funding invested in tackling specific chronic diseases vs the most significant risk factor for chronic diseases is critical. The past half a century war on cancer reveals the limitations of continuing on the path of disease elimination for populations that are approaching the upper limits of the human lifespan.

Strategic innovations in preventative medicine are required if we hope to improve the healthspan of today's ageing populations. To make serious headway in cancer prevention, we must target the most significant risk factor - biological ageing. Despite the limits facing behaviour control, there is good reason for optimism that the development of an applied gerontological intervention could help us achieve the important goal of rate control. Age retardation would ensure we improve the quality of life for older people vs simply preventing death by helping older populations manage multi-morbidity.

When President Nixon declared a "war on cancer" nearly 50 years ago, the success of the war was equated with disease elimination. That is a noble but unrealistic goal. Waging a war against an unrealistic goal is harmful for two reasons. Firstly, it means that large investments of public funds are invested into something that is not attainable (of the 200+ types of cancer, none have been cured or eliminated). Secondly, and more importantly, that investment in disease elimination imposed a hefty opportunity cost. Had those same funds been invested elsewhere, for example, targeting the ageing process itself, it could have yielded the population a much more significant health dividend. The primary challenge for today's ageing populations is not to eradicate cancer mortality but rather to increase the human healthspan.

Cell Therapy to Enhance the Repair Response of the Brain

In today's research materials, researchers present an approach to cell therapy involving the delivery of progenitor cells that are biased to differentiate into astrocytes. Further, the astrocytes so produced are primed to undertake repair activities in the brain. This sort of regenerative approach is in principle applicable to a range of issues, from structural damage to the brain, such as that resulting from injury or stroke, to more subtle issues such as demyelination and the progressively worsening consequences of age-related neurodegeneration.

The advantage of progenitor cells and stem cells, particularly the pluripotent cells that are now easily manufactured by any competent lab, is that they can take on the characteristics of many different cell types. This is also the disadvantage when one wants a very particular type of cell and class of cell behavior. In principle, the robust methods of production of pluripotent cells make it more cost effective to turn out any cell type needed. In practice, the challenge lies in finding the recipe of signals and environment to ensure that the resulting differentiated cells perform in the desired way. This recipe is different for every scenario, and this is one of the reasons why progress towards cell based regenerative therapies is slower than we would all like it to be.

Stem cell therapy promotes recovery from stroke and dementia in mice

The two most common causes of dementia are Alzheimer's disease and white matter strokes - small strokes that accumulate in the connecting areas of the brain. Currently, there are no therapies capable of stopping the progression of white matter strokes or enhancing the brain's limited ability to repair itself after they occur. Now a new study identifies a cell therapy that can stop the progressive damage caused by the disease and stimulate the brain's own repair processes.

The cells used in the therapy are a specialized type of glial cells, which are cells that surround and support neurons in the central nervous system. Researchers evaluated the effects of their glial cell therapy by injecting it into the brains of mice with brain damage similar to that seen in humans in the early to middle stages of dementia. Upon injection, the cells traveled to damaged areas of the brain and secreted growth factors that stimulated the brain's stem cells to launch a repair response. Activating that repair process not only limited the progression of damage, but it also enhanced the formation of new neural connections and increased the production of myelin - a fatty substance that covers and protects the connections.

Patient-derived glial enriched progenitors repair functional deficits due to white matter stroke and vascular dementia in rodents

Astrocytes, axons, and myelin are subjected to major damage during subcortical white matter stroke (WMS), a debilitating disorder leading to cognitive and motor impairments. Previous studies have shown that immature astrocyte transplantation could promote remyelination in rodent models. Now, a team has used a model of WMS in mice to demonstrate that transplantation of glial enriched progenitor cells differentiated from human-induced pluripotent stem cells (hiPSC-GEPs) shortly after stroke matured into a mature astrocyte phenotype and had therapeutic effect on axonal damage, demyelination, and cognitive impairments more effectively than hiPSC-derived neuronal precursor cells. The results suggest that astrocyte precursors have therapeutic potential in stroke.

CDC42 Inhibition Promotes Intestinal Stem Cell Function in Aged Mice

The inhibition of CDC42 is starting to look like a most interesting intervention, based on the animal data produced over the past decade or so. A small molecule approach to CDC42 inhibition, using CASIN, has been assessed in a number of animal studies focused on the hematopoietic stem cell population responsible for generating blood cells and immune cells. Treatment of mice with CASIN results in improved hematopoietic stem cell function, improved immune function, and extended life span. The life span extension was achieved following a single course of treatment with CASIN in middle-aged mice, suggesting that a one-time intervention can produce a lasting improvement in the immune system over the remainder of later life. The state of the immune system itself is, of course, very influential on tissue function and the progression of aging and age-related disease.

Today's open access paper reports on a study focused on a different stem cell population, the intestinal stem cells that support the lining of the gut. Like all stem cell populations, intestinal stem cells decline with age. They become less active, more damaged, and their niches change in ways that promote this lost function. That CASIN treatment can help intestinal stem cell function, and produce improvement in the state of the intestinal epithelium as a result, suggests that the benefits to this therapy are not solely due to improved immune function. If seen to affect two stem cell populations, it may influence numerous other stem cell populations as well.

Suppression of elevated Cdc42 activity promotes the regenerative potential of aged intestinal stem cells

The regenerative capacity of intestine decreases upon aging. Organ homeostasis in the intestine is maintained by intestinal stem cells (ISCs). A decline in ISC function is a main reason for the impaired regeneration of intestinal epithelium upon aging. ISCs express the marker gene Lgr5 and are located next to differentiated Paneth cells at the base of the intestinal crypt. To function properly under homeostasis, ISCs differentiate into highly proliferative transient amplifying (TA) cells. Upon their migration from the crypt base to the villus, TA cells further differentiate into mature cell types including cells in the intestinal villus made of enterocytes, goblet cells, and enteroendocrine cells.

The small RhoGTPase Cdc42 cycles between an active, GTP-bound form (Cdc42-GTP) and an inactive, GDP-bound form. It is thought that biological activity of Cdc42 is regulated by its active form, i.e., the level of Cdc42-GTP. The relative ratio of active Cdc42 is elevated in various tissues of aged mice compared to that of young mice, whereas animals in which Cdc42 activity is increased by genetic means show diverse premature aging phenotypes. It is possible that there is a causative link between Cdc42 activity and aging, and increased Cdc42 activity has indeed been reported to be a causative stem cell intrinsic mechanism for the aging of hematopoietic stem cells (HSCs).

For ISCs, their regeneration capacity declines upon aging, and multiple mechanisms including changes in Wnt signaling could be involved in the process. We show here that an aging-associated increase in the Cdc42 activity in ISCs causes a decline in ISC function and impairs intestinal epithelial regeneration. Suppression of Cdc42 activity can ameliorate ISC regeneration in vitro, and pharmacologic targeting of Cdc42 critically enhances intestinal regeneration upon stress in vivo up on aging. Our studies imply that a tight regulation of the Cdc42 activity is critical for maintaining tissue homeostasis within the intestine during aging and that suppression of aging-related increased Cdc42 activity allows for enhanced tissue regeneration in vivo.

In the Best of Plausible Futures, We Will All Be Occasional Cancer Patients

First generation interventions to target aging are presently in clinical development, or available but not yet widely used. They include senolytic drugs, and a whole range of approaches to upregulate various stress response mechanisms and improve mitochondrial function, among other options. Second generation interventions are under investigation in the scientific community, but remain some years away from earnest clinical development for one reason or another. Most of the possible approaches to the wholesale, reliable replacement of cell populations, for example.

The best of plausible futures is the one in which the most effective of these first and second generation interventions (a) become widely used and (b) produce significant gains in the healthy human life span, of ten to twenty years or more. We'll know one way or another by 2040, and the signs of efficacy should be there earlier than that. I'd wager that we could know by the early 2030s as to whether or not senolytics have a strong effect on human life expectancy in old age, for example. A five year study would be long enough to determine an outcome, but it will take a few years from where we are now in order to get such a study launched. The research community is still waiting on the arrival of compelling human data - to match the great animal data - on suppression of inflammation and improvement of tissue function throughout the body resulting from senolytic treatment.

Cancer will be a consequence of this success. The declines of late life in our species evolved in large part to lower the risk of death by cancer, by reducing cellular activity in damaged environments, at the cost of a slower and more drawn out death by organ failure. Many of the early therapies targeting function in old age are essentially compensatory, dialing up stem cell function or tissue function despite damage, overriding the normal reactions of the body to raised levels of cell and tissue damage. Some therapies do aim to repair cell and tissue damage, and will produce much the same outcome in terms of increased function, but any given collection of treatments will not repair all of the damage. In particular, mutational nuclear DNA damage will be challenging to repair.

Cancer is a numbers game. How many cells, how much cellular activity, how much damage, how long a span of time. Cancer risk is a combination of factors: stochastic mutation in nuclear DNA, the spread of mutations into somatic mosaicism, the inflammatory environment of aged tissues, driven in large part by senescent cells, and the growing incapacity of the aged immune system. To the extent that therapies can address these factors, cancer rates will fall. Cancer is not going to vanish entirely any time soon, however, given the mutation issue. Cancer is an inevitability on any time frame that is long enough, living in a body with nuclear DNA that is damaged enough.

Thus we should all get used to the idea that our lifetime risk of cancer will be notably higher than that of our ancestors, and plan accordingly. Robust, reliable approaches to detecting and destroying cancer are a very necessary part of the panoply of rejuvenation therapies that will be produced over the next few decades. Very broad anti-cancer technologies, such as interference in telomere lengthening, that can be applied to all cancers, will be needed in order to make cost-effective, rapid progress towards the medical control of cancer.

Ultimately, cancer will not be feared by long-lived individuals with access to modern medical technology. A great deal of work remains to get to that point. Once there, however, the cancers that we will suffer - briefly, before they are dealt with efficiency and quickly - will be badges of honor, a mark of the degree to which we have fought back degenerative aging.

Inflammatory Macrophages are Involved in Aortic Aneurysm Formation

An aneurysm is a bulging growth on a blood vessel, at risk of rupture. These can form for a number of reasons, from bacterial infection to age-related weakening of the blood vessel wall. High blood pressure makes the situation worse. An aneurysm of any significant size can cause death or disability when it ruptures. Researchers here note that the inflammatory behavior of macrophage cells appears to be involved in the growth of aneurysms, and targeting a specific gene can adjust that behavior in order to slow aneurysm development in a mouse model of the condition.

A new study investigates a genetic culprit behind abdominal aortic aneurysm, a serious condition that puts people at risk of their aorta rupturing - a potentially deadly event. There are no medications to directly treat the condition and prevent an aneurysm from growing. Current options include things like addressing blood pressure to lower the stress on the arteries and veins running through the body, and making lifestyle changes like quitting smoking. Most people monitor their aneurysm to see if it grows enough to eventually require endovascular or open surgical repair.

For this study, researchers investigated the role of an epigenetic enzyme called JMJD3 in the development of abdominal aortic aneurysm. They found the gene was turned on in both people and mice who had an abdominal aortic aneurysm and that the gene promoted inflammation in monocytes and macrophages. When they blocked the enzyme, it prevented an aneurysm from forming. "Targeting the JMJD3 pathway in a cell specific-manner offers the opportunity to limit abdominal aortic aneurysm progression and rupture."

Retinal Cells that Can Integrate into Tissue and Survive Following Transplantation

One of the biggest challenges in regenerative medicine is ensuring the long-term survival and integration into tissue of any meaningful fraction of transplanted cells. Most transplanted cells simply die. Most early cell therapies achieve benefits via the signaling generated by transplanted cells, in the short period of time before they die. Numerous approaches are under development to try to ensure long-term survival of transplanted cells, but successes have so far been few and far between. Here, researchers report on one of these successes, generating retinal cells that integrate into the retina to produce tissue regeneration.

Researchers have presented the first successful attempt to generate retinal cells that can integrate into the retina. Retinal ganglion cells (RGCs), commonly damaged in glaucoma, are responsible for the transmission of visual information. The scientists managed to not only grow neurons (retinal ganglion cells are considered specialized neurons), but also transplant them into the eyes of mice, achieving the correct ingrowth of artificial retinal tissue. Without treatment, glaucoma can lead to irreversible damage to the optic nerve and, as a result, the loss of part of the visual field. Progression of this disease can lead to complete blindness.

Retinal cells were grown using special organoids, with the tissue formed in a petri dish. These cells were subsequently transplanted into several groups of mice. "Our studies in mice have shed light on some of the basic questions surrounding retina cell replacement, i.e. can donor RGCs survive within diseased host retinas? Or are transplants only possible within young hosts? Using mice in which we used microbeads to artificially elevate intraocular pressure and a model of chemically induced neurotoxicity, we could show that transplanted donor cells survive in disease-like microenvironments. In addition, we could demonstrate that cells survived independent of the donor's age and the location to which the cells were delivered within the retina."

According to the authors, these cells have successfully existed inside mouse retinas for 12 months, which is a significant period for the species. Scientists confirmed that they were able to receive signals from other neurons in the retina; however, the ability of the cells to transmit signals to the brain has yet to be assessed with absolute certainty.

Klotho Reverses Some Muscle Aging in Old Mice, but not in Very Old Mice

Delivery of recombinant klotho, or fragments of klotho, has been an area of interest for the research community. Upregulation of klotho expression has been shown to extend life in mice, and klotho appears to be involved in regulation of tissue aging in a number of different organs. This may all be the consequence of the effects of klotho on declining kidney function with age, given discoveries to date relating to the relationship between klotho, kidney function, and cognitive aging, but investigations are still ongoing, and other more direct connections may yet be found.

Researchers characterised and compared changes in the structure, function, and gene activity in skeletal muscle across the lifespan in mice. They grouped mice into four age categories - young, middle-aged, old and oldest-old - and looked at muscle weight, type of muscle fibers, whether the muscles had accumulated fat, and skeletal muscle function. Although old mice displayed mild sarcopenia, the common clinical features of sarcopenia were only present in the oldest-old mice. Next, they looked at changes in muscle gene activity and found a progressive disruption in genes known to be associated with the hallmarks of aging from the young to the oldest-old mice.

Next, they looked at whether administering Klotho to mice would have beneficial effects on the muscle healing after injury. They found that applying Klotho after muscle injury reduced scarring and increased structures associated with force production in the animals. Injured mice that received Klotho also had better muscle function - such as muscle twitch and force production - and their whole-body endurance improved two-fold.

Finally, the team looked at whether giving the mice Klotho could reverse age-related declines in muscle quality and function. They found that Klotho administration led to some improvements in the old mice: force production was improved by 17% and endurance when supporting whole body weight was 60% greater compared to mice without treatment. But this was only seen in the old mice, and not in the oldest-old animals. Further investigation showed that Klotho affected genes associated with the hallmarks of aging in all age groups, but that the oldest-old mice showed a dysregulated gene response.

Towards a Non-Invasive Biomarker of Aging Based on Volatile Organic Compounds

Researchers here propose building a biomarker of aging based on analysis of what they term the volitome, the mix of volatile organic compounds secreted by the body. It is a reasonable suggestion. Near all such profiles of the aggregated output of cellular behavior (such as proteins in blood, or transcript levels in tissue samples) should contain reflections of the state of health and the level of cell and tissue dysfunction associated with aging or disease. Modern machine learning can quickly identify combinations of factors within this class of data that correlate with chronological age - or with biological age, as measured by mortality risk or incidence of age-related disease. The challenge then is to understand how these biomarkers connect to underlying processes of aging, as until that is known, it is hard to use them to assess potential age-slowing or rejuvenation therapies.

Our team and others have proposed a number of potential biomarkers, such as epigenetic clocks, serum N-glycans, and GDF15, associated to aging or age-related diseases. Moreover, during the last years, our group also studied the "volatilome", i.e. a set of endogenous Volatile Organic Compounds (VOCs) resulting from body's metabolism. VOCs are low-weight carbon-based molecules detectable in sweat, exhaled breath, blood, urine, and feces, and that, except for blood, are considered non-invasive diagnostic biomarkers. VOCs are involved in different physiological processes and VOCs profile may differ with age, gender, physiological status, reflecting the metabolic conditions of an individual and represents her/his "odor-fingerprint".

We wondered whether this kind of biomarkers could be useful also to identify people's age, as suggested by previous studies. We then investigated VOCs profile in healthy aging and longevity in humans by analyzing the VOCs in both urine and feces that better mirror the endogenous metabolism of the organism. The samples derived from volunteers of different age, including centenarians and their offspring that represent a sort of "super-controls" to identify potential VOCs biomarkers of successful aging and longevity. We have reported the existence of specific patterns of urinary and fecal VOCs that can discriminate subjects of different age, from young to centenarians, and, even more interesting, centenarians' offspring from age-matched controls.

Among the different VOCs identified in our study, we found that the fecal VOCs belonging to aldehydes class are less abundant in the group of young with respect to the groups of elders, that generally display a greater susceptibility to inflammation and diseases. This finding is in agreement with literature data indicating that metabolites belonging to aldehydes class are produced during inflammatory processes and are involved in several age-related diseases, such as atherosclerosis, cardiovascular diseases, neurodegenerative diseases, and metabolic disorders. These observations suggested that the different VOCs patterns may likely reflect changes in metabolic processes associated with age and health status.

Reviewing Myostatin in Muscle Growth, and Efforts to Produce Myostatin-Targeted Therapies

Myostatin is one of the better targets for enhancement therapies from the point of view of feasibility and existing data on its effects. Myostatin suppresses muscle growth via intracellular signaling. A range of possible methods exist to interfere in this process, some of which have been trialed in human patients: reducing production of myostatin, binding to circulating myostatin with antibodies to ensure clearance, preventing myostatin from binding to cell surface receptors in other ways, upregulation of follistatin, an antagonist to myostatin, and so forth. Myostatin loss of function mutants, natural and artificial, exist for a range of mammalian species, including humans. Beyond a much greater than usual muscle growth, there do not appear to be obvious long-term issues in these individuals.

Current research findings in humans and other mammalian and non-mammalian species support the potent regulatory role of myostatin in the morphology and function of muscle as well as cellular differentiation and metabolism, with real-life implications in agricultural meat production and human disease. Myostatin null mice (mstn-/-) exhibit skeletal muscle fiber hyperplasia and hypertrophy whereas myostatin deficiency in larger mammals like sheep and pigs engender muscle fiber hyperplasia. Myostatin's impact extends beyond muscles, with alterations in myostatin present in the pathophysiology of myocardial infarctions, inflammation, insulin resistance, diabetes, aging, cancer cachexia, and musculoskeletal disease.

In this review, we explore myostatin's role in skeletal integrity and bone cell biology either due to direct biochemical signaling or indirect mechanisms of mechanotransduction. In vitro, myostatin inhibits osteoblast differentiation and stimulates osteoclast activity in a dose-dependent manner. Mice deficient in myostatin also have decreased osteoclast numbers, increased cortical thickness, cortical tissue mineral density in the tibia, and increased vertebral bone mineral density. Further, we explore the implications of these biochemical and biomechanical influences of myostatin signaling in the pathophysiology of human disorders that involve musculoskeletal degeneration.

The pharmacological inhibition of myostatin directly or via decoy receptors has revealed improvements in muscle and bone properties in mouse models of osteogenesis imperfecta, osteoporosis, osteoarthritis, Duchenne muscular dystrophy, and diabetes. However, recent disappointing clinical trial outcomes of induced myostatin inhibition in diseases with significant neuromuscular wasting and atrophy reiterate complexity and further need for exploration of the translational application of myostatin inhibition in humans.

Sirtuin 6 in Mammalian Aging

A great deal of time and effort has been spent on investigating the biochemistry of sirtuins in numerous species, with as yet very little to show for it in practical terms. Early attempts to produce viable age-slowing interventions via upregulation of sirtuin 2 were a comprehensive failure, and it is entirely plausible that recent interest in sirtuin 6 will go the same way. This class of metabolic tinkering has a terrible track record, mixed results in mice that then fail to translate to humans, and the reasonable expectation is that this will continue to be the case for the foreseeable future.

The role of sirtuins in senescence was discovered in budding yeast, where overexpression of SIR2 increases replicative lifespan. Subsequently, It was reported that elevated sirtuin levels increase lifespan in the nematode C. elegans and the fruitfly Drosophila, indicating an evolutionarily ancient role of sirtuins in longevity assurance. Mammals contain seven sirtuins, SIRT1-7, which are categorized by their different subcellular localization, unique binding substrates, and diverse enzymatic activities. Recently the direct role of SIR2 in aging and lifespan extension has been disputed, but the overwhelming majority of significant results still support a potential role for SIRT6 in regulating mammalian lifespan.

SIRT6 was shown to extend lifespan in mammals, while deficiency of SIRT6 was associated with progeria, an accelerated aging disorder. Studies have confirmed the important roles for SIRT6 in protecting against aging and disease pathologies: SIRT6-deficient mice are small and have severe metabolic defects, and by 2-3 weeks of age, they develop abnormalities that are usually associated with aging. However, SIRT6 overexpression led to an increase in lifespan in male mice. Mechanistically, SIRT6, being a histone deacetylase, inhibits the transcription of transcription factors related to senescence, maintains the structure of telomere chromatin, prevents genomic instability after DNA damage, and protects cells from senescence.

A Small Human Study of Short Term Nicotinamide Mononucleotide Supplementation

Declining levels of NAD+ in cells is one of the proximate causes of loss of mitochondrial function with age. A number of approaches to increasing levels of NAD+ in cells involve using supplements that are derived from vitamin B3. Nicotinamide mononucleotide (NMN) is one of these, but has to date far less published human evidence for its effects than is the case for nicotinamide riboside (NR), making the small study noted here interesting. In general, the evidence for vitamin B3 derived compounds to increase NAD+ in older people is good, while the evidence for that increase to then produce benefits to health is mixed at best. For further consideration, regular exercise appears to be better at increasing NAD+ levels than this sort of supplementation, based on human trial data, and we have a fairly good idea as to the effect size of exercise when it comes to mortality and risk of age-related disease.

A small clinical trial of postmenopausal women with prediabetes shows that the compound NMN (nicotinamide mononucleotide) improved the ability of insulin to increase glucose uptake in skeletal muscle, which often is abnormal in people with obesity, prediabetes or Type 2 diabetes. NMN also improved expression of genes that are involved in muscle structure and remodeling. However, the treatment did not lower blood glucose or blood pressure, improve blood lipid profile, increase insulin sensitivity in the liver, reduce fat in the liver or decrease circulating markers of inflammation as seen in mice.

Among the women in the study, 13 received 250 mg of NMN orally every day for 10 weeks, and 12 were given an inactive placebo every day over the same period. "Although our study shows a beneficial effect of NMN in skeletal muscle, it is premature to make any clinical recommendations based on the results from our study. Normally, when a treatment improves insulin sensitivity in skeletal muscle, as is observed with weight loss or some diabetes medications, there also are related improvements in other markers of metabolic health, which we did not detect in our study participants."

The remarkable beneficial effects of NMN in rodents have led several companies in Japan, China and in the U.S. to market the compound as a dietary supplement or a neutraceutical. The U.S. Food and Drug Administration is not authorized to review dietary supplement products for safety and effectiveness before they are marketed, and many people in the U.S. and around the world now take NMN despite the lack of evidence to show clinical benefits in people.

Accelerating Progress Towards the Reversible Cryopreservation of Organs

There is a growing level of interest and funding for the goal of reversible cryopreservation of whole organs. If achieved, this would radically improve the logistics of organ donation, allowing organs to be kept indefinitely before use. Proof of principle demonstrations have been carried out, but the field has lacked the funding and impetus to rapidly build upon that starting point. Hopefully this will change. The ability to reliably vitrify and thaw large tissue sections with minimal ice crystal formation, cell death, or other structural damage will add legitimacy to the goal of human cryopreservation, storing patients at the time of death to allow the possibility of future revival in an environment of far more capable biotechnology.

When scientists in the 1950s tried to cool hamsters to 0°C and rewarm them, it didn't go great. In 2002, things looked rosier when a scientist chilled a single rabbit kidney down to -130°C, then rewarmed it and transplanted it into a live rabbit, where it worked for 48 days. Then not much else succeeded for the next decade. Chilling and re-warming organs, it turns out, is really, really hard. Ice crystals that form during cooling and re-warming cause massive physical damage to cells and whole tissues.

To nudge the field forward, in 2014 a group of entrepreneurs formed the nonprofit Organ Preservation Alliance (OPA). In the years since, the OPA coordinated numerous conferences and publications and prompted the creation of a National Science Foundation technology roadmap for organ cryopreservation, all of which bolstered more than 100 million in new cryobiology funding from U.S. science agencies, donors, and industry. Now, in what OPA sees as a culmination of their efforts, the organization is launching a philanthropic fund to support two academic research centers focused on cryopreservation. "It's been a renaissance for the field of cryobiology. These two centers build on that momentum, and new technologies have come into sharp focus within the same timeframe."

Resarchers will focus on safely cooling tissues and organs by infusing the vasculature and surroundings with cryoprotective solutions and iron oxide nanoparticles coated with silica. After rapid cooling to a very low temperature, a process called vitrification, the organ or tissue is stored. Upon rewarming, the team activates the distributed nanoparticles via a radiofrequency field, heating the cryopreserved tissue rapidly and uniformly. Finally, the cryoprotective agents and nanoparticles can be safely removed prior to transplant or other biomedical use. "Scientists are coming back to ideas they had in the 1980s, but now with the right technology to carry them out. It's incredibly exciting. Back then, we didn't have the right tools, but now it feels like we really do. We hope we're about to make this really big step forward."

Targeting Cellular Senescence in the Aging Vascular Endothelium

Senescent cells accumulate with age throughout the body. Their secreted signals generate chronic inflammation, change surrounding cellular behavior for the worse, and disrupt tissue maintenance and tissue function. In mice, targeted removal of these cells with senolytic drugs reverses aspects of aging and extends life span. In humans, early clinical trials of these drugs are underway. As noted in this short review paper, there is evidence for cellular senescence to be involved in vascular aging. Senescent cells may contribute to the formation of aneurysms. Senescent macrophages may accelerate the progression of atherosclerosis. Senescent cells promote vascular calcification. And so forth.

Since the initial clinical trials for senolytic drugs are focused on other age-related conditions, it may be some years before there is robust data for vascular aging to show how well the results in mice translate to humans. The first generation senolytics are easily obtained compounds, however, and at least one of these treatments comes with human data to show that it does indeed clear much the same fraction of senescent cells as it does in mice. The self-experimentation and medical tourism communities will be employing these treatments well in advance of further formal publications on their efficacy.

The endothelial cell (EC) monolayer forms the inner cellular lining of all blood vessels forming a critical interface between blood and tissue. Vascular endothelium is involved in physiological functions, which include regulation of blood fluidity, hemostasis and clotting, vascular tone, immune responses, inflammation, angiogenesis, and metabolism. Dysfunction of the endothelium is a major contributor to cardiovascular diseases (CVD) such as stroke, atherosclerosis, hypertension, and diabetes. Chronological aging is the dominant risk factor for CVD, cancer and neurodegenerative diseases and indeed endothelial dysfunctions including arterial stiffening, impaired neovascularization, and loss of tissue-barrier function are evident in age-related disease.

EC dysfunction is a well-accepted hallmark of age-related vascular dysfunction, with the initiation of abnormal inflammatory and thrombotic circuits, arterial stiffening and oxidative stress being central to its biology. Importantly, for our understanding of vascular aging, senescent EC accumulate in aging tissues and contribute to tissue dysfunction.

The field of senolytics, drugs that selectively eliminate senescent cells, is gaining momentum. Dasatinib and Quercetin (D+Q) were some of the first senolytics, which remove senescent cells in vitro and in progeroid mice through targeting of the anti-apoptotic pathways in senescence. Long term oral treatment of D+Q have been shown to improve vascular function in aged or atherosclerotic mice. The D+Q combination has been shown to efficiently reduce senescence cell burden in phase I trials for several senescence-related diseases such as diabetic kidney disease.

Although senescence was initially considered as an all-encompassing phenotypic change, it is now apparent that each cell type exhibits an unique and distinguishing senescence phenotype, one that may also be tissue specific. Hence our understanding of endothelial senescence is still in its infancy. Current findings have indicated that specific depletion of senescent cells reverses age-related changes and prolongs life span. However, caution should be urged as cellular senescence also plays important physiological roles such as in tissue development, wound healing, and tumor inhibition. To achieve optimal success in targeting senescence it will be imperative to have a thorough knowledge of the senescent cell type at play in disease, and their spatiotemporal expression in order to deliver the most appropriate senolytic, senomorphic or drug combination.

Bone Aging, Cellular Senescence, and Osteoporosis

The accumulation of senescent cells throughout the body with age contributes to the chronic inflammation of aging, as well as to many age-related conditions. Clearance of these cells produces a sizable and beneficial reversal of aspects of aging and the progression of age-related disease in mice. We will soon enough know whether this is also true in humans. Given the number of biotech companies presently working on senolytic therapies capable of targeted destruction of senescent cells, many clinical trials for senolytics will be undertaken in the years ahead. As noted below, osteoporosis is one of the age-related conditions in which growing numbers of senescent cells are implicated as a contributing cause.

Substantial alterations in bone architecture occur with aging, including decreases in trabecular thickness and number, cortical bone loss and porosity, and increase in marrow adiposity. These changes reflect imbalances in bone remodeling, favoring a net loss of bone caused predominately by increased osteoclast activity in postmenopausal women, as well as both poor bone formation and increased osteoclast activity in older men and women. Cellular senescence and apoptosis of osteoblasts and osteocytes account for much of the aging phenotype in bone, although appear to be independent of estrogen-mediated effects.

There is growing evidence to suggest that cellular senescence in bone can be triggered by reactive oxygen species, DNA damage, telomere dysfunction, and heterochromatin changes, depending on the cell type. miRNAs serve to modulate critical switching points, such as those between osteogenesis and adipogenesis, and aspects of the senescence program. The senescence-associated secretory phenotype (SASP) likely mediates local and even distant deleterious effects of senescent cells, especially by myeloid cells and osteocytes. Radiation-induced bone loss provides an accelerated aging bone model that recapitulates many aspects of age-related bone loss. With both physiological and premature bone aging, genetic and pharmacologic approaches to clearing senescent cells prevent, delay, or ameliorate osteoporosis in mouse models. Senolytic compounds are currently being evaluated in interventional clinical trials.

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