Fight Aging!

The SENS Research Foundation is one of the most important of the scientific and advocacy institutions presently working to make sure that viable approaches to rejuvenation advance to the point at which they can be commercially developed for use in human medicine. If you are deciding on where to make a charitable contribution for the end of 2020, then look no further than this organization, currently running their year end fundraiser. The next $300,000 of donations are presently tripled by matching funds provided by supporters - so jump in while that is the case!

SENS Research Foundation 2020 End of Year Fundraiser

Thanks to a generous matching challenge by Oculus co-founder Michael Antonov, up to $600,000 donated before the end of 2020 will be doubled! But wait, there's more. A team of SRF supporters - Brendan Iribe, Karl Pfleger, Jim Mellon, Dave Fisher, Christophe Cornuejols and Larry Levinson - have joined forces to offer a further $300,000 matching grant. This pool of funds runs in parallel to Michael's challenge, which means the next $300,000 donated will be tripled!

The SENS Research Foundation has long specialized in unblocking areas of research relevant to aging that have received too little attention and funding. Notable successes include the discovery of bacterial enzymes to degrade persistent molecular waste such as A2E, a cause of retinal degeneration, as well as the creation of cyclodextrin molecules that can sequester 7-ketocholesterol, a toxic metabolic byproduct that contributes to numerous age-related and other conditions. The former program led to preclinical development at LysoClear, a part of the Ichor Therapeutics portfolio, and the latter gave rise to the spin out company Underdog Pharmaceuticals. Further, the SENS Research Foundation funded work on the tools needed to work with glucosepane, an advanced glycation endproduct that forms the majority of persistent cross-links in aged human tissue, and that led to Revel Pharmaceuticals, a company funded to develop candidate cross-link breakers.

There are other examples and other projects still underway on mechanisms necessary to produce human rejuvenation. The SENS Research Foundation gets things done, and funds provided go a long way towards ensuring that our personal futures are long and healthy. The only way to get there is to build better medicine, and that starts with the sort of work carried out at the SENS Research Foundation, supported by everyday philanthropists and people of vision, just like you and I.

It is the common wisdom that fat tissue becomes harder to lose with age, that metabolism tilts in the direction of wanting to retain that fat. The results of this study are a counterpoint, suggesting that, given the same adherence to the usual weight loss protocol of eating fewer calories, older people can in fact lose weight just as readily as younger people. Visceral fat tissue is harmful to long-term health in numerous ways, but particularly through the generation of chronic inflammation that accelerates the onset and progression of all of the common fatal age-related conditions. The only thing worse than gaining excess fat tissue is holding on to it over time, and letting the damage and dysfunction to your tissues accumulate as a result.

Obese patients over the age of 60 can lose an equivalent amount of weight as younger people using only lifestyle changes, according to a new study that demonstrates that age is no barrier to losing weight. The researchers hope that their findings will help to correct prevailing societal misconceptions about the effectiveness of weight loss programmes in older people, as well dispel myths about the potential benefits of older people trying to reduce their weight.

For this retrospective study, researchers randomly selected 242 patients who attended an obesity service between 2005 and 2016, and compared two groups (those aged under 60 years and those aged between 60 and 78 years) for the weight loss that they achieved during their time within the service. All patients had their body weight measured both before and after lifestyle interventions administered and coordinated within the obesity service, and the percentage reduction in body weight calculated across both groups.

When compared, the two groups were equivalent statistically, with those aged 60 years and over on average reducing their body weight by 7.3% compared with a body weight reduction of 6.9% in those aged under 60 years. Both groups spent a similar amount of time within the obesity service, on average 33.6 months for those 60 years and over, and 41.5 months for those younger than 60 years. The hospital-based program used only lifestyle-based changes tailored to each individual patient, focusing on dietary changes, psychological support, and encouragement of physical activity. Most of the patients referred to the obesity service were morbidly obese with a BMI typically over 40.

Link: https://warwick.ac.uk/newsandevents/pressreleases/age_is_no

Researchers here note a modest life extension in mice resulting from long-term treatment with low doses of a PPARγ agonist drug, started in mid-life. This is thought to be an adjustment that acts to suppress inflammation and improve insulin metabolism, both strongly connected to the way in which cellular metabolism determines pace of aging. The size of the effect in mice is small enough to think that it would have little effect on life span in our species, however. Effects derived from this sort of metabolic adjustment have a much larger impact on life span in short-lived species than they do in long-lived species, as most of the relevant stress response mechanisms connecting metabolism to environmentally induced variations in the pace of aging evolved as a part of the life-extending response to calorie restriction. A seasonal famine is a long time to a mouse, not so long to a human, so only the mouse evolves a sizable gain in life span when these stress response mechanisms are trigger.

Aging leads to a number of disorders caused by cellular senescence, tissue damage, and organ dysfunction. It has been reported that anti-inflammatory and insulin-sensitizing compounds delay, or reverse, the aging process and prevent metabolic disorders, neurodegenerative disease, and muscle atrophy, improving healthspan and extending lifespan. Here we investigated the effects of PPARγ agonists in preventing aging and increasing longevity, given their known properties in lowering inflammation and decreasing glycemia.

Our molecular and physiological studies show that long-term treatment of mice at 14 months of age with low doses of the PPARγ ligand rosiglitazone (Rosi) improved glucose metabolism and mitochondrial functionality. These effects were associated with decreased inflammation and reduced tissue atrophy, improved cognitive function, and diminished anxiety- and depression-like conditions, without any adverse effects on cardiac and skeletal functionality. Furthermore, Rosi treatment of mice started when they were 14 months old was associated with an 11% median lifespan extension.

A retrospective analysis of the effects of the PPARγ agonist pioglitazone (Pio) on longevity showed decreased mortality in patients receiving Pio compared to those receiving a PPARγ-independent insulin secretagogue glimepiride. Taken together, these data suggest the possibility of using PPARγ agonists to promote healthy aging and extend lifespan.

Link: https://doi.org/10.1111/acel.13267

A score or so different types of amyloid can form in the human body, each a protein that can become altered or misfolded in a way that encourages other molecules of the same protein to also alter or misfold. These broken proteins aggregate together into sheets and fibrils, forming solid deposits in and around cells that interfere with the normal function of tissues, or are actively toxic. Transthyretin is one such protein, and transthyretin amyloidosis is present to some degree in all older people. Evidence of recent years suggests that it is a factor in 10% of heart failure cases in old people in general, and it may be the dominant cause of cardiac mortality in supercentenarians, those aged 110 or older.

The open access paper noted here is an interesting overview of the mechanisms by which amyloidosis occurs in the case of transthyretin, in the context of trying to predict who is most at risk and should therefore be treated. Eidos Therapeutics has a treatment in the late stage of development that interfers enough with the mechanisms of transthyretin aggregation to be worth the effort, though as for most such lines of development it will initially be targeted at cases in which transthyretin is mutated in ways that accelerate amyloidosis, rather than as a preventative therapy for the entire population. More aggressive degradation of amyloid will likely be needed, such as via the use of catabodies, a line of work at an earlier stage of development at Covalent Bioscience, but nonetheless promising.

Proposing a minimal set of metrics and methods to predict probabilities of amyloidosis disease and onset age in individuals

The rate of synthesis of transthyretin (TTR) is constant. For proteostasis, the rate of removal of TTR must equal the rate of synthesis. TTR in plasma is largely in the tetrameric form, (TTR)4, but dissociates to give very low, but significant concentrations of dimers and monomers. Removal of TTR from plasma proceeds via monomers.

Monomers undergo two processes that remove them from solution, proteolysis or aggregation. The combined rates of these two pathways equals the total rate of monomer removal, which is also equal to the rate of production of monomer via dissociation of tetramer. Depending on the relative rates, either of the two reaction pathways could account for anywhere from 100% to 0% of the rate of monomer removal. The critical monomer concentration for aggregation is unknown, however the cause of aggregation develops slowly over time. Once amyloidosis begins, the rate of development of amyloidosis is determined by the rate of monomer incorporation into various aggregates that lead to fibrils and amyloids.

Destabilizing tetramer by pleiotropic mutations leads to greater dissociation of monomer and a higher, variant-dependent concentration of TTR monomer in plasma. Mutations are not required for TTR amyloidosis formation; point mutations only modify the equilibrium concentrations. Amyloidosis caused by wild-type TTR follows the same mechanism as amyloidosis caused by variants of TTR and thus should be considered as variants of the same disease for purposes of clinical studies.

Amyloidosis begins when the rate of TTR proteolysis decreases relative to the rate of amyloid formation and monomer concentration increases sufficiently to allow significant oligomerization into fibrils and amyloids. The cause of a decrease in the rate of proteolysis of TTR remains to be identified. When the tetramer is stabilized by drugs or stabilizing mutations, the concentration of tetramer will increase in plasma to a steady-state level determined by the rate of proteolysis.

Researchers here report on progress towards non-invasive retinal scanning as an approach to determining Alzheimer's disease risk in the very early stages of progression towards the condition. The path to Alzheimer's is marked by years of a slow accumulation of amyloid-β, an antimicrobial peptide that can misfold to form solid aggregates. While the evidence suggests that amyloid-β can on its own cause mild cognitive impairment, it remains to be determined as to whether it also causes the later stages of Alzheimer's, the chronic inflammation and tau aggregation that kills large numbers of brain cells. It may be a side-effect of other processes, such as persistent viral infection, senescent cell accumulation, and the like. Fortunately, that present lack of knowledge may not matter when it comes to the use of amyloid-β as a marker of risk and progression towards Alzheimer's disease.

Researchers have identified certain regions in the retina - the lining found in the back of the eye - that are more affected by Alzheimer's disease than other areas. The findings were from a clinical trial involving people older than 40 who were showing signs of cognitive decline. In the trial, investigators used a noninvasive technique known as sectoral retinal amyloid imaging to capture retinal images in participants. The retina, which is directly connected to the brain, is the only central nervous system tissue accessible for patient-friendly, high-resolution and noninvasive imaging.

The images were then analyzed using a new process that could identify certain peripheral regions in the retina that corresponded better to brain damage and cognitive status. In studying the images, scientists could detect patients with an increased buildup of retinal amyloid protein, signifying a higher likelihood of developing Alzheimer's disease or cognitive impairments. These findings build upon pioneering research in 2010 in which researchers identified a pathological hallmark of Alzheimer's disease, amyloid beta-protein deposits, in retinal tissues from deceased patients. The team then developed a methodology to detect retinal amyloid beta-protein plaques in living patients suffering from the disease.

Link: https://www.cedars-sinai.org/newsroom/retinas-new-potential-clues-in-diagnosing-treating-alzheimers/

There are now a variety of epigenetic clocks, weighted combinations of the methylation status of various CpG sites on the genome in various different tissues. The epigenetic marks of DNA methylation change constantly in response to circumstances and cell activities, but some of these changes are characteristic of the aged tissue environment, and thus correlate well with the burden of damage and dysfunction that causes manifestations of aging. A person more greatly damaged will tend to exhibit an epigenetic age higher than chronological age, a phenomenon referred to as age acceleration.

Epigenetic clocks are derived from the analysis of large amounts of epigenetic data obtained from study population of different ages, rather than from any understanding of how and why age-related epigenetic changes take place. Cell metabolism and epigenetics are very complex, and it remains unclear in near all cases as to why specific changes occur, and how those changes relate to the underlying processes of aging. Still, one can certainly run the numbers to decide which of the clocks are better or worse than others when it comes to assessing the burden of aging.

The aging process is characterized by the presence of high interindividual variation between individuals of the same chronical age prompting a search for biomarkers that capture this heterogeneity. Epigenetic clocks measure changes in DNA methylation levels at specific CpG sites that are highly correlated with calendar age. The discrepancy resulting from the regression of DNA methylation age on calendar age is hypothesised to represent a measure of biological ageing with a positive or negative residual signifying age acceleration or deceleration respectively.

The present study examines the associations of four epigenetic clocks - Horvath, Hannum, PhenoAge, GrimAge - with a wide range of clinical phenotypes (walking speed, grip strength, Fried frailty, polypharmacy, Mini-Mental State Exam (MMSE), Montreal Cognitive Assessment (MOCA), Sustained Attention Reaction Time, 2-choice reaction time), and with all-cause mortality at up to 10-year follow-up, in a sample of 490 participants in the Irish Longitudinal Study on Ageing (TILDA).

Horvath Age Acceleration (AA) and HannumAA were not predictive of health; PhenoAgeAA was associated with 4 of 9 outcomes (walking speed, frailty, MOCA, MMSE) in minimally adjusted models, but not when adjusted for other social and lifestyle factors. GrimAgeAA by contrast was associated with 8 of 9 outcomes (all except grip strength) in minimally adjusted models, and remained a significant predictor of polypharmacy, frailty, and mortality in fully adjusted models. Results indicate that the GrimAge clock represents a step-improvement in the predictive utility of the epigenetic clocks for identifying age-related decline in an array of clinical phenotypes promising to advance precision medicine.

Link: https://doi.org/10.1093/gerona/glaa286

Michael Antonov is one of a number of high net worth individuals who are interested in accelerating progress towards a first generation of comprehensive rejuvenation therapies, targeting all of the mechanisms of aging in order to cure age-related disease and extend healthy life spans. The SENS Research Foundation remains one of the most important organizations in this space, focused on the scientific advances needed in order to repair the molecular damage that causes aging. Degenerative aging and age-related disease exists because the normal operation of youthful metabolism produces forms of damage as a side-effect: varieties of molecular waste that are both toxic and hard to break down; mutational damage to DNA; accumulating senescent cells; cross-links in the extracellular matrix; and so forth.

Senescent cell accumulation can already be repaired to some degree, thanks to advances in science that led to senolytic drugs, the first class of rejuvenation therapy worthy of the name. The others will follow at a pace determined by how much funding goes into the necessary research programs.

SENS Research Foundation is delighted to announce a matching grant from the Antonov Foundation. The Antonov Foundation will match every dollar donated between now and the end of the campaign on December 31, 2020 - up to a total of $600,000!

SENS Research Foundation is incredibly grateful for this generous investment in the future we all hope to create - a future where getting older brings wisdom and experience but not disease, suffering, and pain. Thank you, Michael Antonov, and thank you to all who have donated so far to our end of year campaign. And if you're still planning on donating, there's no better time to do it than on Giving Tuesday this December 1!

Michael Antonov said: "I've followed and supported SENS research over the last few years and am excited to up my commitment this year because their organized, practical approach to combating aspects of aging, such as breaking down of cross-links, rejuvenating the mitochondria, and clearance of senescent cells has potential to help human lives and achieve age reversal in the near future."

Over the past decade, thousands of visionary folk in our community have donated more than $10 million to the SENS Research Foundation. This support has produced clear progress towards the goal of rejuvenation. Neglected areas of research have been revived, companies created to start commercial development of therapies, and the field of rejuvenation research has gained legitimacy and support. There is still so much to accomplish yet, of course! So I am very pleased to see that Michael Antonov is stepping up to provide a sizable amount of funding to the SENS Research Foundation in the form of a matching grant for the 2020 year end fundraiser. It is Giving Tuesday soon, and we should all use that opportunity to support the future that we'd like to see, one in which aging is controlled by medical science, and there is no more suffering in old age.

Researchers are interested in provoking the body into growing additional blood vessels that can bypass areas of damage. Most of this work is focused on restoring long term supply of blood to heart tissue following a heart attack, and thus on regrowth in an environment of damage and damage-related signaling. It would be perhaps more interesting to develop means of growing additional redundant blood vessels prior to that point, in the normal signaling environment. This could greatly reduce the damage done by a blockage that would ordinarily cause a heart attack, and slow the progression into heart failure caused by narrowing of blood vessels. This all compares poorly to developing means of prevention of atherosclerosis, the cause of blood vessel narrowing, rupture, and blockage, but even given a cure for atherosclerosis, there is a lot to be said for having redundant routes of blood supply to major organs.

Cardiovascular disease is the leading cause of mortality and ischemic heart disease is a major cause of death worldwide. Coronary vessels that nourish the heart develop from three main sources, the endocardium on the inner surface of the hearts blood-filled chambers being one of the major contributors. In normal conditions, the adult heart can no longer generate new blood vessels from the endocardium, because the endocardium-to-coronary vessel transition is blocked by a connective tissue wall beneath the endocardium.

In a recently published study researchers show that the VEGF-B growth factor can be used to activate the growth of vessels inside of the heart during cardiac ischemic damage. This novel finding opens the possibility that vessels emerging from the inner side of the heart could be further developed for the treatment of myocardial infarction, which results from insufficient delivery of oxygen to cardiac tissue. In normal conditions, blood nourishes the adult heart through coronary vessels.

VEGF-B (vascular endothelial growth factor) belongs to a family of growth factors that regulate the formation of blood- and lymphatic vessels. Earlier attempts to utilize another growth factor gene, VEGF-A, to grow new vessels in the heart have failed, mostly due to the leakiness of the vessels and increased inflammation caused by VEGF-A, but not by VEGF-B. Re-activation of the embryonic vessel growth program in adult endocardium could be a new therapeutic strategy for cardiac neovascularization after myocardial infarction. For possible future clinical use, the function of these vessels and their blood flow has to be further studied to ensure that they really increase transport of oxygen and nutrients into the cardiac muscle.

Link: https://www.helsinki.fi/en/news/health-news/a-bypass-route-for-the-coronary-vessels-in-the-heart

Cells become senescent and cease replication in response to damage, a toxic environment, or reaching the Hayflick limit. Such cells near all self-destruct or are destroyed by the immune system. In later life, however, they begin to linger and accumulate. This is an issue, as the secretions of senescent cells are quite harmful when sustained over the long term, producing chronic inflammation and disruption of tissue structure and function. The cells of the immune system are no less subject to the burden of cellular senescence than is the case for any other cell type, in fact arguably more so given that infection results in an aggressive replication of immune cells to meet the challenge, pushing those cells towards the Hayflick limit faster than they can be reinforced by newly created immune cells. Senescent immune cells are likely an important contributing cause of the systemic chronic inflammation of aging, as well as of many age-related conditions.

As we age, we accumulate cells in many organs that exhibit signs of DNA damage, have poor proliferative capacity, and are highly secretory. These cells are senescent, defined as being in a state of cell cycle arrest associated with phenotypic and functional changes. While transient senescence is a beneficial mechanism earlier in life, the accumulation of senescent cells with increasing age leads to organ dysfunction, driving inflammation and may underlie many age-related diseases such as atherosclerosis, osteoarthritis, neurodegenerative diseases, and cirrhosis.

While senescence was first discovered in fibroblasts and extensively worked on in other non-leukocytic cells, it has become increasingly clear that immune cells undergo senescence as well. Within the immune system, the existence of non-proliferative leukocyte populations that have high capacity for biologically active mediator secretion has been recognized for many decades, albeit under a different name. These are the effector T lymphocytes that secrete pro-inflammatory cytokines and cytotoxic granules but do not proliferate after activation. Recent studies show that these cells also harbour DNA damage, short telomeres, low telomerase activity, and engage signalling pathways associated with cellular senescence. Therefore, the terms effector T cells and senescent T cells may be synonymous and refer to the same T cell populations.

The extent of T cell proliferation the acute phase of a viral infection drives T cells to senescence. These cells are still susceptible to apotosis but can persist given sufficient antiapototic cytokines in tissue niches. It can be argued that senescent T cells derive from a subpopulation of effector T cells that do not undergo apoptosis, instead becoming senescent and lingering long term. In this article we discuss data on T cell senescence, how it is regulated and evidence for novel functional attributes of senescent T cells. We discuss an interactive loop between senescent T cells and senescent non-lymphoid cells and conclude that in situations of intense inflammation, senescent cells may damage healthy tissue. While the example for immunopathology induced by senescent cells that we highlight is cutaneous leishmaniasis, this situation of organ damage may apply to other infections, including COVID-19 and also rheumatoid arthritis, where ageing, inflammation and senescent cells are all part of the same equation.

Link: https://doi.org/10.1111/acel.13272

Every cell contains a herd of hundreds of mitochondria, organelles descended from ancient symbiotic bacteria. The primary purpose of mitochondria is to package the chemical energy store molecule adenosine triphosphate (ATP) that is needed to power cellular processes. Each mitochondrion contains one more copies of a small circular genome, the mitochondrial DNA. This mitochondrial DNA is unfortunately poorly protected and repaired in comparison to nuclear DNA. Accumulation of damage in the form of mutations is thought to be an important contributing cause of mitochondrial dysfunction in aging, leading to less ATP and thus disruption of cell and tissue function.

The data of recent years indicates that not all mutations in mitochondrial DNA are equal when it comes to causing problems. Point mutations seem to be quite well tolerated, as illustrated by the heterozygous PolG mutator mice. These mice exhibit very high levels of point mutations in mitochondrial DNA due to a loss of function mutation in one of the two copies of PolG, an enzyme involved in mitochondrial DNA replication and repair. Deletion mutations, on the other hand, are the path to sizable and detrimental changes, as they can remove or disable electron transport chain proteins. This can result in mitochondria that outcompete their undamaged peers in replication efficiency or resistance to the quality control mechanisms of mitophagy, take over a cell, render it dysfunctional, and export harmful reactive molecules into surrounding tissue.

Age-induced mitochondrial DNA point mutations are inadequate to alter metabolic homeostasis in response to nutrient challenge

Mitochondria are essential for respiration and the regulation of diverse cellular processes; thus, mitochondrial dysfunction is believed to underlie a variety of metabolic and aging-related diseases. Mutations in the mitochondrial genome are thought to drive mitochondrial dysfunction and have been implicated in aging-related diseases; however, whether mtDNA mutations are causal or consequent of metabolic dysfunction remains unclear. The polymerase gamma (PolG) "mutator" mouse is a model of intrinsic mitochondrial dysfunction and was employed for this study to determine whether mtDNA mutations are sufficient to drive metabolic abnormalities and aging-associated insulin resistance and adiposity.

Mice harboring a homozygous PolG loss of proofreading 3′-5′ exonuclease function mutation (PolGmut/mut) develop mtDNA point mutations at a rate that far exceeds mutations observed in aged wild-type (WT) animals and humans. The mtDNA point mutations that accumulate in young PolGmut/mut mice (~136-fold increase versus WT mice) manifest a variety of preadolescent phenotypic abnormalities including progeroid-like symptoms throughout maturation as well as premature death (~12-16 months of age). Because of the complexity of the early-onset aging, we studied the PolG heterozygous (PolG+/mut) mouse, which lacks progeroid-like symptoms despite a supraphysiological mtDNA point mutation frequency (~30-fold greater mutation load in PolG+/mut versus WT mice). Furthermore, male and female PolG+/mut mice show no significant difference in lifespan versus WT animals (tested up to 800 days of age).

Based on previous reports, we hypothesized that an increased mtDNA point mutation frequency in PolG+/mut mice would promote mitochondrial dysfunction and accelerate the development of insulin resistance during aging. We examined specific aspects of metabolism in male PolG+/mut mice at 6 and 12 months of age under three dietary conditions: normal chow (NC) feeding, high-fat feeding (HFD), and 24-hr starvation. We performed mitochondrial proteomics and assessed dynamics and quality control signaling in muscle and liver to determine whether mitochondria respond to mtDNA point mutations by altering morphology and turnover. In the current study, we observed that the accumulation of mtDNA point mutations failed to disrupt metabolic homeostasis and insulin action in male mice, but with aging, metabolic health was likely preserved by countermeasures against oxidative stress and compensation by the mitochondrial proteome.

Astrocytes are supporting cells in the brain, and contribute to the correct function of neurons in numerous ways. It is plausible that widespread disruption of astrocyte function could lead to cognitive issues. Researchers here offer evidence to suggest that tau pathology in Alzheimer's disease extends beyond neurofibrillary tangles made up of phosphorylated tau in neurons, and also includes excessive amounts of tau in astrocytes. This appears to change astrocyte behavior in ways that negatively affect memory, but as always in Alzheimer's disease, the animal models used to assess these effects are quite artificial and may or may not be relevant to the human condition.

Tau tangles are an integral part of Alzheimer's disease (AD) pathology, appearing in the hippocampus in early stage disease and then gradually spreading throughout the brain. Their accumulation closely mirrors cognitive decline. Researchers have focused on tau's role in neuron dysfunction and death. What about other cells? Researchers looked for tau tangles in different areas of the hippocampus in tissue samples from healthy controls and from people with AD. As expected, they found them in the AD samples, but the pathology was not equally distributed; there were hot spots in certain areas, including the hilus. "The hilus is seen as a highway between the dentate gyrus and CA3 region within the hippocampus, so most researchers do not pay much attention to what happens there. It turns out to be very important."

Zooming in on the astrocytes in the hilus, researchers saw they were packed with three-repeat (3R) tau in the AD tissue samples. This isoform contributes to the 3R/4R type of neurofibrillary tangles found in Alzheimer's. The amount of 3R tau in the astrocytes correlated with tau tangles and with amyloid-β plaques in the surrounding tissue, suggesting the 3R tau accumulation may be downstream of other AD pathologies. Oddly enough, researchers found no increase in phosphorylated forms of tau in the astrocytes or any evidence of tangles in these cells. He speculated that this might be because these hilar astrocytes cells do not phosphorylate the protein as easily as neurons do, or that tau is dephosphorylated by the astrocytes.

Does this 3R tau accumulation affect the astrocytes or their surrounding neurons? To test this idea in a mouse model, researchers overproduced tau in mouse hippocampi. Researchers injected lentiviruses carrying a gene for human 3R tau into the hippocampi of 3-month-old wild-type mice. Two weeks later, they verified that the human 3R tau was expressed only in hilar astrocytes. Within these astrocytes, mitochondria languished in the cell bodies, rather than travelling to the astrocyte arms that support neurons. Mitochondrial function also suffered; the organelles replenished less often, and they produced much less ATP than usual.

Still, neurons looked normal for the most part, with no signs of neuronal death. However, neurogenesis had faltered, and the treated mice had fewer parvalbumin-positive inhibitory neurons in the dentate gyrus than controls. The number of inhibitory synapses also collapsed. Parvalbumin-producing neurons are like the pacemakers of the brain, modulating γ-frequency oscillations, which is important for working memory. Indeed, the 3R mice had weaker γ activity in the hippocampus and had trouble finding a hidden platform in a water maze. Otherwise, they seemed to behave normally. Taken together, the results suggested that accumulation of tau in hilar astrocytes compromised the function of hippocampal inhibitory neurons.

Link: https://www.alzforum.org/news/research-news/does-astrocyte-tau-cause-dementia

In heterochronic parabiosis, one joins the circulatory system of an old mouse and a young mouse. The old mouse exhibits reversal of manifestations of aging, and the young mouse exhibits an acceleration of manifestations of aging. Research initially focused on factors in young blood that might be producing benefits in older individuals, and work continues on GDF11 as one such factor, with Elevian heading towards human trials. More data has accumulated in recent years to suggest that the bulk of the effect is due to harmful factors in old blood, however, and benefits in old mice in parabiosis are simply a matter of diluting those factors.

A series of experiments run in recent years have results in ways to safely and simply dilute blood in old mice, using as few additional components as possible, in order to make the results quite clearly the outcome of dilution alone. As demonstrated here, diluting blood in old mice results in reduced inflammation and consequent improvement in tissue function. This reinforces the idea that the research community should focus on what makes old blood harmful, rather than on what might be making young blood beneficial.

Parabiosis studies have yielded a plethora of insights regarding mechanisms that underlie the aging of stem cell niches. It was shown that old partners have better health in multiple tissues when they shared blood with a younger animal. A prominent interpretation of heterochronic parabiosis is that aging is malleable and that the aging process can be slowed or even reversed. Brain aging in particular is associated with a progressive loss of functionality and is thought to be in large part the result of an excessive activation of microglia, the brain-resident myeloid cells. The age-related declines in brain function and cognition (among many other functions in the body) were once considered inevitable and permanent. Parabiosis studies, interestingly, have challenged this notion by illustrating the plasticity of brain maintenance and function after changing the age of the blood.

Several systemic proteins and young plasma infusions were suggested to influence the plasticity of brain aging, albeit with some controversy to the actual age-specific levels of some of these candidate factors, such as GDF11, B2M, CCL11, and TIMP2. There was also a lack of health span increase in young plasma infusion studies; and while safety trials were successful, the young blood approaches have not been demonstrated to be effective in improving the health of the brain or any other tissue in clinic. In concert, heterochronic blood transfusion exchange experiments have shown that in the absence of the organ sharing and environmental enrichment of parabiosis, young blood does not rejuvenate the old brain.

As we investigate and form an evolutionary conserved paradigm of systemic rejuvenation, our data demonstrated that young blood is not the primary determinant, and instead, dilution of old blood plasma yields a robust resetting of the systemic signaling milieu to youth and health, rejuvenating multiple tissues. The study of the brain in that report was limited to hippocampal neurogenesis; here we expand the work to other important facets of brain health: neuroinflammation and cognition. Our data demonstrate that neuroinflammation (specifically the activation of microglia), declines and the cognitive capacity of old mice, improves after a single treatment of blood dilution. Considering that therapeutic plasma exchange (TPE) is FDA approved, this study suggests a use of this procedure to prevent, attenuate, and possibly even reverse the degenerative and inflammatory diseases of the brain.

Link: https://doi.org/10.1007/s11357-020-00297-8

There is a great deal of interest in cellular senescence these days. The accumulation of senescent cells in later life is robustly demonstrated to be an important mechanism of aging, and one that can be reversed via the application of what have come to be called senolytic therapies. In mice, the application of senolytics extends life and reverses the progression of numerous age-related conditions. Senescent cells are harmful, even though their numbers are never very large, because they secrete a mix of signals that provoke inflammation, tissue remodeling, and changes in cell activity. Sustained over the long term, this contributes meaningfully to age-related declines and diseases.

Chronic kidney disease is one such condition. Treatment options are limited, while the inexorable loss of kidney function in patients produces increasingly serious downstream issues throughout the body. Evidence has accumulated for cellular senescence to be a major contributing cause of chronic kidney disease. It is widely recognized in the research community that senolytic therapies are a promising new approach to treatment of the condition. An ongoing clinical trial, watched with interest, is using the senolytic combination of dasatinib and quercetin in chronic kidney disease patients, with preliminary results reported last year indicating that this does in fact remove senescent cells. We will have to wait and see for the rest of the data.

Senescence and the Aging Immune System as Major Drivers of Chronic Kidney Disease

Age-related pathologies are a major global disease burden, with potentially half of all morbidities being attributable to aging. Inflammation (or "inflammaging") is one of the main causative factors contributing to disease progression, and has been described in various age-related pathologies, including type 2 diabetes (T2D) and cardiovascular disease. While being beneficial in the acute stages of an insult, inflammation increasingly fails to resolve with age, leading to changes in both cellular phenotypes and immune system composition. Senescence pathways are induced by, as well as potentiate, chronic inflammation, with increased cellular senescence being observed in various age-related diseases. Cellular senescence is characterized by a stable growth arrest and a proinflammatory secretome, which potentiates low grade chronic inflammation, thereby building a positive feedback loop, gradually exacerbating its effects on the body.

With a prevalence of approximately 44% in the elderly population (of 65 years and older), chronic kidney disease (CKD) presents a major disease burden in an aging population. Therapies for late stage CKD including dialysis and renal transplantation carry a significant burden for patients, and the outcome is often poor; therefore, there is a significant need for early diagnosis and novel therapies targeting mechanisms driving the disease. CKD is associated with chronic inflammation, elevated levels of cellular senescence, as well as immune system dysfunction.

Senescent cells may both be a phenotype of age-related inflammatory disease, as well as the cause for disease progression. Thereby two models of disease progression exist: One in which senescent cells arise from local tissue injury, promoting senescence in neighboring cells in a paracrine manner. Alternatively, immune clearance may be impaired, thereby allowing the accumulation of senescent cells. Distinguishing between these two models becomes pivotal when exploring potential new treatments of CKD.

Much of the immune dysregulation is governed by the presence of proinflammatory cytokines, and uremia, or by pre-existing comorbidities such as high blood pressure or diabetes. In addition to the levels of inflammatory markers, an elevated white blood cell count is predictive of CKD development. This suggests various modes of pathogenesis, with the immune system, senescence, and inflammation at its core. Cellular senescence and immunosurveillance occur in conjunction, increased cellular senescence due to chronic inflammation increases the demand for immune clearance; however, as described above, uremia and inflammation lead to dysfunction of the immune system, thereby establishing a positive feedback loop in which more senescent cells drive inflammation and immune dysregulation which, in turn, cause more senescence.

Cells become senescent in response to reaching the Hayflick limit on replication, suffering molecular damage, or in an environment of tissue injury. A senescent cell ceases replication and begins to secrete an inflammatory mix of cytokines and growth factors, the senescence-associated secretory phenotype (SASP), rousing the immune system and provoking changes in surrounding cell behavior. Near all senescent cells are quickly destroyed, but with age these cells linger. The signaling that is useful in the short term for cancer suppression (by removing damaged and potentially damaged cells in the earliest stages of cancer) or regeneration from injury (by provoking greater cell activity) becomes very harmful when sustained for the long-term. Senescent cell accumulation is an important contributing cause of aging and age-related disease.

Cellular senescence is a phenomenon that has been known about for a long time. During recent years, it has gained growing interest as its causal involvement in the aging process has been corroborated by several experimental findings. Because of this, several groups and companies are developing senolytic approaches that aim to remove senescent cells from aged animals in the hope of achieving a rejuvenation and life extension effect. However, at the same time, cellular senescence is also seen as an anti-cancer strategy, which raises the question why interfering with an anti-cancer mechanism should increase life span?

The argument that antagonistic pleiotropy explains the anti-tumorigenic as well as the pro-tumorigenic and inflammatory properties of senescent cells is problematic, since there are multiple ways imaginable to break the link between positive and negative effects. In this paper, we discussed an alternative idea for the evolution of cellular senescence that focuses on the involvement of senescent cells in the repair of cell and tissue damage. From such a viewpoint, many properties of the SASP make much more sense and are actually beneficial. Additionally, the recent finding that also post-mitotic cells can display characteristics of cellular senescence, agrees well with this idea. While post-mitotic cells benefit from triggering a healing and repair mechanism, they do not profit from an anti-cancer process.

According to our interpretation, the negative effects of cellular senescence only emerge because the clearance of senescent cells by the immune system, once the repair process has finished, is imperfect. Senescent cells represent a very heterogeneous population, depending on the original cell type and on how senescence was triggered. We therefore proposed that there is a continuum of turnover rates, since the immune system is more or less capable of recognizing this range of subtypes. A mathematical model, which for simplicity only uses two types of senescent cells (removable and non-removable), achieves an excellent fit to experimental data. Interestingly, our model also predicts a slowdown of senescent cell turnover with age, in our case explained by an accumulation of non-removable senescent cells relative to removable ones.

For obvious reasons, there are high hurdles for the destruction of body cells. We propose that for this reason, the optimal strategy is for the immune system to accept a small fraction of false negatives, leading to the slow accumulation of senescent cells in the body. This, in turn, then leads to life-threatening consequences like chronic inflammation (inflammaging), degenerative diseases, and cancer. In this interpretation of cellular senescence, there needs to be a balance between beneficial effects (i.e., wound healing and tissue repair) and negative consequences (i.e., accumulation of senescent cells with inflammation and diseases).

To see how this differs from the idea that cellular senescence is an anti-cancer strategy, we have to return to the questions that we posed earlier. Why did evolution not break the connection of the antagonistic effects and why do organisms not rely exclusively on apoptosis as anti-cancer strategy? The discussed proposal makes it more difficult to break the antagonistic effects, since there is always a trade-off between overlooking too many senescent cells (false negatives) and killing too many healthy body cells (false positives). However, the situation can be improved quantitatively by somehow enabling the immune system to better recognize senescent cells. Indeed, it may be that this has already happened during the evolution of long-lived species, which accumulate senescent cells at a slower pace than short-lived species.

If this outline of the evolution of cellular senescence is correct, it also follows that the removal of accumulated senescent cells is a good strategy, as long as it does not interfere with the primary function of this process. Thus, a brief senolytic treatment would be suitable, while a chronically administered drug might be problematic.

Link: https://doi.org/10.1111/acel.13270

Glial scars made up of activated astrocyte cells form following injury to nervous system tissue in mammals, and while protective in some ways, this scarring blocks functional regeneration. It is an important mechanism that limits the degree to which nerves and brain tissue can regenerate, and thus a target for the regenerative medicine community. Researchers here demonstrate a gene therapy approach that causes glial scars in the brain to regenerate into functional neural tissue. This line of work seems well worth keeping an eye on.

Injuries in the central nervous system (CNS) often causes neuronal loss and glial scar formation. We have recently demonstrated NeuroD1-mediated direct conversion of reactive glial cells into functional neurons in adult mouse brains. Here, we further investigate whether such direct glia-to-neuron conversion technology can reverse glial scar back to neural tissue in a severe stab injury model of the mouse cortex. Using an adeno-associated virus (AAV)-based gene therapy approach, we ectopically expressed a single neural transcription factor NeuroD1 in reactive astrocytes in the injured areas.

We discovered that the reactive astrocytes were efficiently converted into neurons both before and after glial scar formation, and the remaining astrocytes proliferated to repopulate themselves. The astrocyte-converted neurons were highly functional, capable of firing action potentials and establishing synaptic connections with other neurons. Unexpectedly, the expression of NeuroD1 in reactive astrocytes resulted in a significant reduction of toxic A1 astrocytes, together with a significant decrease of reactive microglia and neuroinflammation. Furthermore, accompanying the regeneration of new neurons and repopulation of new astrocytes, new blood vessels emerged and blood-brain-barrier (BBB) was restored. These results demonstrate an innovative neuroregenerative gene therapy that can directly reverse glial scar back to neural tissue, opening a new avenue for brain repair after injury.

Link: https://doi.org/10.3389/fncel.2020.594170

In today's open access paper, researchers propose the use of sodium 4-phenylbutyrate to inhibit protein glycation, reducing the creation of advanced glycation endproducts (AGEs) in the body, and thus limit the contribution of this class of compounds to aging and disease. AGEs are quite varied and comparatively poorly studied; it is still the case that new ones are being found, and there is considerable room for debate on which AGEs are more or less important to aging and outcomes of metabolic diseases such as diabetes. Short-lived AGEs, easily broken down, are inflammatory via the receptor for AGEs (RAGE), and this may be their primary contribution to aging and disease. Persistent AGEs, on the other hand, can form lasting cross-links that stiffen tissues such as blood vessel walls, causing conditions such as hypertension.

In studies like the one noted below, it is usually quite unclear as to whether or not a useful range of AGEs are being inhibited. In other words, whether the approach is better applied to treating metabolic disorders, to lower the large amounts of short-lived AGEs that are causing inflammation, or whether it might help to slow the progressive accumulation of cross-links with age. Further, the AGEs relevant to aging and disease are thought (and in some cases shown) to be different between mammalian species. This has been quite problematic in past attempts to produce drugs that can break down AGEs in order to produce therapeutic benefit. For example, this is why the development of the AGE-breaker drug alagebrium failed.

Ultimately, however, a therapy that has to be applied constantly in order to slow the accumulation of damage (such as persistent AGE cross-links in tissues) is a poor alternative to a therapy that can be applied intermittently to remove damage (such as by breaking down existing persistent AGE cross-links). Prevention of contributing causes of aging is not that helpful to those who are already old. That makes the class of approach here less interesting when compared with, say, the AGE-breaking enzymes under development at Revel Pharmaceuticals.

Sodium 4-phenylbutyrate inhibits protein glycation

Glycation is a non-enzymatic chemical reaction that occurs between a ketone or aldehyde group of fructose or glucose and an amino acid residue or the hydroxy-group of a protein or lipid, and is often referred to as the Maillard reaction. Protein glycation occurs through a complex series of very slow reactions in the body, including the formation of the stable Amadori-lysine products (Schiff bases). These give rise to advanced glycation end-products (AGEs).

It is hypothesized that the production and accumulation of AGEs have causal roles in the development of the complications associated with aging and lifestyle-related diseases, such as diabetes, atherosclerosis, and hyperlipidemia. Furthermore, the production and accumulation of AGEs are involved in the development of other diseases, such as cardiovascular diseases, cerebrovascular disorders, chronic renal failure, Alzheimer's disease, and Parkinson's disease. Therefore, the identification of safe treatments that can inhibit glycation is required, as they may exhibit anti-aging effects, or serve as a therapeutic option for prevention of diseases associated with glycation.

In the present study, the ability of sodium 4-phenylbutyrate (PBA) on inhibition of glycation was assessed. In vitro, PBA inhibited the glycation of albumin and collagen by up to 42.1% and 36.9%, respectively. Furthermore, when spontaneously diabetic KK mice were administered PBA (20 mg/day) or vehicle orally, glycosuria developed rapidly in the control mice, but after 6 weeks, only one treated mouse was glycosuric. In addition, the weight gain and HbA1c levels were significantly lower in the treated mice compared with the untreated mice. These results suggested that PBA also inhibited glycation in vivo. Further studies are required to determine whether PBA may be effective for the therapy or prevention of aging or lifestyle-related diseases caused by the accumulation of AGEs. The method of administration and the side-effects of PBA have already been established as PBA is already used clinically. Therefore, the repurposing of PBA for reducing AGE levels may be a potential option to reduce complications associated with aging.

The research materials here examine the age-related changes in metabolite production in the gut microbiome and correlate those changes with the presence of amyloid-β in the brain, a feature of Alzheimer's disease. It is a good companion piece to another recently published paper that links changes in microbial population abundance and Alzheimer's disease. The question of causation arises, as always, but it is plausible to think that the aging of the gut microbiome, influential on chronic inflammation in the body, contributes to the risk of Alzheimer's disease, which is a condition that appears to be driven in large part by chronic inflammation.

Intestinal bacteria can influence the functioning of the brain and promote neurodegeneration through several pathways: they can indeed influence the regulation of the immune system and, consequently, can modify the interaction between the immune system and the nervous system. Lipopolysaccharides, a protein located on the membrane of bacteria with pro-inflammatory properties, have been found in amyloid plaques and around vessels in the brains of people with Alzheimer's disease. In addition, the intestinal microbiota produces metabolites - in particular some short-chain fatty acids - which, having neuroprotective and anti-inflammatory properties, directly or indirectly affect brain function.

"To determine whether inflammation mediators and bacterial metabolites constitute a link between the gut microbiota and amyloid pathology in Alzheimer's disease, we studied a cohort of 89 people between 65 and 85 years of age. Some suffered from Alzheimer's disease or other neurodegenerative diseases causing similar memory problems, while others did not have any memory problems. Using PET imaging, we measured their amyloid deposition and then quantified the presence in their blood of various inflammation markers and proteins produced by intestinal bacteria, such as lipopolysaccharides and short-chain fatty acids."

This work thus provides proof of an association between certain proteins of the gut microbiota and cerebral amyloidosis through a blood inflammatory phenomenon. Scientists will now work to identify specific bacteria, or a group of bacteria, involved in this phenomenon. This discovery paves the way for potentially highly innovative protective strategies - through the administration of a bacterial cocktail, for example, or of prebiotics to feed the "good" bacteria in our intestine.

Link: https://www.eurekalert.org/pub_releases/2020-11/udg-lba111320.php

Stressing cells a little leads to overall benefits, as maintenance mechanisms such as autophagy are upregulated to more than compensate for any damage. This is known as hormesis, and it is one of the reasons why exercise, calorie restriction, radiation, and heat can produce health benefits at appropriate dose levels. Researchers here explore one of the links between oxidative damage and the beneficial responses to that damage. In theory, a better view of these linking mechanisms may lead to better ways to mimic the effects of mild stress in order to improve long term health.

Researchers studied the enzyme Tsa1, which is part of a group of antioxidants called peroxiredoxins. Previous studies of these enzymes have shown that they participate in yeast cells' defences against harmful oxidants. But the peroxiredoxins also help extend the life span of cells when they are subjected to calorie restriction. The mechanisms behind these functions have not yet been fully understood.

It is already known that reduced calorie intake can significantly extend the life span of a variety of organisms, from yeast to monkeys. Several research groups have also shown that stimulation of peroxiredoxin activity in particular is what slows down the ageing of cells, in organisms such as yeast, flies, and worms, when they receive fewer calories than normal through their food. "Now we have found a new function of Tsa. Previously, we thought that this enzyme simply neutralises reactive oxygen species. But now we have shown that Tsa1 actually requires a certain amount of hydrogen peroxide to be triggered to participate in the process of slowing down the ageing of yeast cells."

Surprisingly, the study shows that Tsa1 does not affect the levels of hydrogen peroxide in aged yeast cells. On the contrary, Tsa1 uses small amounts of hydrogen peroxide to reduce the activity of a central signalling pathway when cells are getting fewer calories. The effects of this ultimately lead to a slowdown in cell division and processes linked to the formation of the cells' building blocks. The cells' defences against stress are also stimulated - which causes them to age more slowly.

Link: https://www.chalmers.se/en/departments/bio/news/Pages/Cell-ageing-can-be-slowed-by-oxidants.aspx

An interesting open access paper was recently published on the effects of hyperbaric oxygen treatment on telomere length and cellular senescence in immune cells taken from blood samples. I use the word "interesting" quite deliberately, because that is exactly and all that this research is. The paper is appropriately formal and modest on that front, but this attitude doesn't extend to the rest of the publicity, unfortunately. When one runs a business based around offering hyperbaric oxygen treatment, one must make hay while the sun shines, and extract every last drop of marketing juice from every study funded. Hence there are media articles out there at the moment breathlessly telling us that hyperbaric oxygen treatment reverses aging. This is ridiculous, and only makes it harder for the better end of the industry to make progress.

Per the paper, hyperbaric oxygen treatment causes average telomere length to grow by ~20% and markers of cellular senescence to decrease by ~35% in populations of circulating immune cells. This doesn't tell us that hyperbaric oxygen treatment is an amazing rejuvenation therapy, any more than the NAD+ and mitochondrial function data for exercise tells us that exercise is an amazing rejuvenation therapy. In both cases we already know the bounds of the possible. We know that these interventions don't turn older people into notably younger people. If we're calling exercise and hyperbaric oxygen treatment rejuvenation therapies, then the term "rejuvenation therapy" is meaningless.

What this does reinforce is the point that peripheral blood immune cell parameters can be very disconnected from the overall state of aging. We know that telomere length as assessed in these cells is a truly terrible measure of aging. Circulating immune cells are prone to large variations in the pace of celular replication in response to circumstances. Immune cells replicate aggressively when provoked by the presence of pathogens or other issues requiring a coordinated immune response. Telomere length shortens with every cell division in somatic cells: in immune cells, telomere length thus has a very wide spread across individuals, varies day to day, is just as influenced by infection status and other environmental factors as it is by aging. It is just not all that helpful as a measure of aging, and downward trends with age are only seen in the statistics for large study populations.

It seems plausible that the same is true of cellular senescence in immune cells. Cells become senescent when they hit the Hayflick limit on cellular replication. Throughout much of life, the senescence of immune cells is likely more determined by replication pace (and thus immune challenges, the burden of infection) than by aging. And that is before we even get to the point that the authors of this paper used a less than standard measure of senescence, one for which it is possible to argue that it may or may not actually be representative of the burden of senescent cells in immune populations. Overall this data is all interesting, but I suspect that it tells us more about the poor relevance of the metrics chosen to anything other than the deeper aspects of immune function.

If hyperbaric oxygen treatment removed ~35% of senescent cells throughout the body, it would already be well known as a reliable therapy for arthritis, a way to reverse chronic kidney disease, a way to suppress inflammatory conditions, and an effective treatment for numerous chronic diseases of aging. In mice, removing a third of senescent cells via senolytic drugs produces reliably large and beneficial outcomes, while hyperbaric oxygen treatment does not. So clearly it is not globally clearing senescent cells - and nor should any responsible party be trying to present reductions in senescent immune cells as indicative of global senolytic effects throughout the body. What is observed here is an effect limited to the way in which the immune system is functioning. There is some evidence for hyperbaric oxygen treatment to improve resistance to infectious disease such as influenza, and that is interesting in and of itself, but I feel that much of what is going on here is an attempt by certain parties to jump onto the longevity industry bandwagon, rather than responsibly focusing on a realistic view of what can be achieved with their chosen intervention.

Hyperbaric oxygen therapy increases telomere length and decreases immunosenescence in isolated blood cells : a prospective trial

Hyperbaric oxygen therapy (HBOT) utilizes 100% oxygen in an environmental pressure higher than one absolute atmospheres (ATA) to enhance the amount of oxygen dissolved in body's tissues. Repeated intermittent hyperoxic exposures, using certain HBOT protocols, can induce physiological effects which normally occur during hypoxia in a hyperoxic environment, the so called hyperoxic-hypoxic paradox. In addition, it was recently demonstrated that HBOT can induce cognitive enhancements in healthy aging adults via mechanisms involving regional changes in cerebral blood flow. On the cellular level, it was demonstrated that HBOT can induce the expression of hypoxia induced factor (HIF), vascular endothelial growth factor (VEGF), and sirtuin (SIRT), stem cell proliferation, mitochondrial biogenesis, angiogenesis, and neurogenesis. However, no study to date has examined HBOT's effects on telomere length and senescent cell accumulation.

Thirty-five healthy independently living adults, aged 64 and older, were enrolled to receive 60 daily HBOT exposures. Whole blood samples were collected at baseline, at the 30th and 60th session, and 1-2 weeks following the last HBOT session. Peripheral blood mononuclear cells (PBMCs) telomeres length and senescence were assessed. Telomeres length of T helper, T cytotoxic, natural killer and B cells increased significantly by over 20% following HBOT. The most significant change was noticed in B cells. There was a significant decrease in the number of senescent T helpers by -37.30% post-HBOT. T-cytotoxic senescent cell percentages decreased significantly by -10.96% post-HBOT.

In conclusion, the study indicates that HBOT may induce significant senolytic effects including significantly increasing telomere length and clearance of senescent cells in the aging populations.

Sense of smell declines with advancing age, a loss of capacity already correlated with broader neurodegeneration and progression towards cognitive impairment and dementia. Here, researchers correlate the loss of sense of small with numerous other aspects of aging, as well as type 2 diabetes, a condition associated with a greater risk of age-related disease and mortality because most diabetics are significantly overweight. Excess fat tissue accelerates aging via mechanisms such as increased generation of senescent cells and increased chronic inflammation.

Olfactory dysfunction is common in aging and associated with dementia and mortality. However, longitudinal studies tracking change in olfactory ability are scarce. We sought to identify predictors of interindividual differences in rate of olfactory identification change in aging. Participants were 1780 individuals, without dementia at baseline and with at least 2 olfactory assessments over 12 years of follow-up (mean age = 70.5 years; 61.9% female), from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K). Odor identification was assessed with the Sniffin' Sticks. We estimated the impact of demographic, health, and genetic factors on rate of olfactory change with linear mixed effect models.

Advancing age, manufacturing profession, history of cerebrovascular disease, higher cardiovascular disease burden, diabetes, slower walking speed, higher number of medications, and the APOE ε4 allele were associated with accelerated odor identification decline. Multi-adjusted analyses showed unique associations of age, diabetes, and ε4 to olfactory decline. In 1531 participants who remained free of dementia during follow-up, age, cardiovascular disease burden, and diabetes were associated with accelerated decline. Of these, age and diabetes remained statistically significant in the multi-adjusted model.

In conclusion, demographic, vascular, and genetic factors are linked to rate of decline in odor identification in aging. Although some olfactory loss may be an inevitable part of aging, our results highlight the importance of vascular factors for the integrity of the olfactory system, even in the absence of dementia.

Link: https://doi.org/10.1093/gerona/glaa221

Cytomegalovirus is a persistent herpesvirus that is problematic in a few populations, largely harmless in the short term for everyone else, largely unnoticed by those infected, and widely prevalent in the population. Near everyone is infected by the time old age arrives. Unfortunately, CMV appears to be a major factor in the age-related decline of the adaptive immune system, possibly by causing ever more immune cells to become uselessly specialized to target it, leaving too few immune cells for other tasks. This sort of runaway resource misallocation in the immune system is a large problem in the elderly, given that the thymus, where new T cells of the adaptive immune system mature, is near entirely atrophied by late life, reducing the supply of new cells to a trickle. Effective vaccination will help this situation, but there is good reason to think that, for the oldest to benefit, it must be accompanied by selective destruction of cytomegalovirus-focused immune cells, and restoration of the supply of new immune cells.

A research team says it has identified a key marker that will help speed effective vaccine designs for cytomegalovirus (CMV), the most common congenital infection worldwide. The researchers describe an immune surrogate that demonstrates when a vaccine has elicited the necessary antibodies that protect against CMV infection. The finding is already being applied to screen potential vaccines.

"Despite the high global burden of disease, vaccine development to prevent infection remains hampered by challenges in generating protective immunity. The most efficacious CMV vaccine candidate tested to date is a soluble glycoprotein B (gB) subunit vaccine with MF59 adjuvant (gB/MF59), which achieved 50% protection in multiple phase 2 clinical trials. The vaccine-elicited immune responses that conferred this protection have remained unclear. We investigated the humoral immune correlates of protection from CMV acquisition in populations of CMV-seronegative adolescent and postpartum women who received the gB/MF59 vaccine. We found that gB/MF59 immunization elicited distinct CMV-specific immunoglobulin G (IgG)-binding profiles and IgG-mediated functional responses in adolescent and postpartum vaccinees, with heterologous CMV strain neutralization observed primarily in adolescent vaccinees."

"We determined that protection against primary CMV infection in both cohorts was associated with serum IgG binding to gB present on a cell surface but not binding to the soluble vaccine antigen, suggesting that IgG binding to cell-associated gB is an immune correlate of vaccine efficacy. Supporting this, we identified gB-specific monoclonal antibodies that differentially recognized soluble or cell-associated gB, revealing that there are structural differences in cell-associated and soluble gB are relevant to the generation of protective immunity."

"Our results highlight the importance of the native, cell-associated gB conformation in future CMV vaccine design. CMV has been recognized as a top priority for vaccine development for more than 20 years, yet we remain without an approved vaccine. This work provides a way to assure that current and future vaccine candidates stimulate an effective immune response."

Link: https://www.genengnews.com/topics/drug-discovery/immune-surrogate-finding-may-accelerate-cmv-vaccine-development/

There is a certain constituency in this world of ours whose members look at the far side of middle age with a fatalistic gloom, envisaging the last, decrepit light before the darkness. The age of 75 stands out in the present discussion on this topic only for a noted op-ed touting a hoped end to life at that point. That voice isn't alone. Many people, perhaps even most people, express the desire to die on some schedule in late life, if asked. Perhaps a few years older than their peers, because hierarchy is important to we primates, but nonetheless, the present view is that after middle age we should be shutting up shop, tiding up the shelves for the next tenant, and generally getting out of the way, in the most permanent fashion possible.

This view starts with the desire not to suffer, and then broadens out from that into a consensus view on the shape of human life that is considered less carefully and challenged perhaps less often than it should be. Everyone is taught from youth - via schooling, stories, myth, and the all too real health issues of older relatives - that old age is a degeneration, a fall into a broken body and a broken mind, filled with pain and an ultimate return to the weakness and dependency of childhood. That this is set in stone, never to be changed. This is an insufferable fate for most, and so it is decided that death, historically the only other option on the table, is a liberation.

But there are other options on the table when taking into consideration the fact that we live in an era of exceptionally rapid progress in all technologies. There is cryonics, for one, potentially reversible low-temperature preservation of the body and brain for a future capable of rebuilding and restoring a youthful life. Then there is progress in more established medical science: simply said, the therapies for age-related disease and dysfunction ten years from now will be far better than those that exist today, and that trend will continue, decade by decade. We are also presently in the midst of an enormous and beneficial disruption in this trend, in that the research and development community is now directly targeting the mechanisms that cause aging, whereas in the past they did not.

I am middle aged. My old age, creeping ever closer with each passing year, will likely be one of comparative fitness, vigor, and youthful function. The nascent longevity industry of today, producing a handful of ways to turn back the molecular damage that causes aging, will become a world-spanning colossus in the years ahead. It will provide a broad range of effective rejuvenation therapies that will put an end to the chronic inflammation and immune system failures of aging, to the frailty and loss of mitochondrial function, and a host of diseases and declines and causes of suffering and mortality will near vanish along the way. The first rejuvenation therapies already exist; the first few score companies developing such therapies already exist. It is easy to see a lengthy future from where we stand now, if one only cares to learn a little about the work presently underway.

Why I Hope to Be Alive at 75

Ezekiel Emanuel is best known for writing a controversial article in 2014, headlined "Why I Hope to Die at 75", in which he strongly rejects the desire to live beyond the age of 75 and expresses his opinion that continuing to live after such an age is meaningless. At age 63, he is getting closer to the age at which he thinks life is pointless, and I believe that a large reason why he is so pessimistic about life beyond 75, whether he realizes it or not, is based on the current state of medicine. This line of reasoning does not take into account how medicine, and in particular how we treat aging could change in the next decade or two.

Current medicine does a great job at keeping people alive for longer, but they often have to live with one or more chronic diseases. Given that, I am not surprised that Emanuel is not enamored with living a long life, especially as that could entail being disabled, bed-bound, or otherwise suffering a poor quality of life as the result of debilitating age-related diseases. However, things could be different in the not so distant future, and being 75 could see the majority of people far more fit, healthy, and vibrant than ever before in human history thanks to advances in aging research. Therapies that directly target aging could potentially make people biologically younger (in particular their immune systems) and much more able to withstand COVID-19 and other diseases.

The decline of the immune system is a key reason why the elderly are most susceptible to infectious diseases such as COVID-19, and there has been considerable interest in the rejuvenation of the immune system in recent years. Dr. Greg Fahy from Intervene Immune has had some early success with thymus rejuvenation in a small human pilot study and demonstrated that it is possible to cause the thymus, which shrinks and loses its capacity to produce T cells during aging, to regrow and resume production of those cells. Another example of immune rejuvenation is currently being developed by Samumed, a biotechnology company that is developing drugs that target the Wnt pathway to restore it to youthful function.

These are only some of the examples of why healthy life expectancy could rise significantly in the near future, and there are plenty of reasons to remain future positive. This is the future direction of medicine and healthcare, a world where being 75 does not mean you are thrown on the scrap heap and where people like Emanuel will no longer feel that life has no meaning. I am confident that in such a world, being 75 would not be the burden he thinks it will be, and this is why I hope to be alive at 75.

Microglia are innate immune cells of the brain, similar to macrophages in the rest of the body, but with a larger portfolio of activities. They are not just chasing down pathogens and cleaning up molecular waste, but are also deeply involved in maintaining the function and connectivity of neurons in brain tissue. Here, researchers note that several genetic variants that are either problematic or protective when it comes to Alzheimer's disease risk and progression affect the ability of microglia to clear amyloid-β aggregates from brain tissue. While therapies targeting amyloid-β accumulation have so far failed to produce meaningful clinical benefits in patients, perhaps because other processes have taken over as the dominant cause of pathology in later stage Alzheimer's disease, increased aggregation of amyloid-β is clearly associated with the condition, and is equally clearly the cause of toxic biochemistry that can harm cells.

Alzheimer's disease is the most common form of dementia with more than 40 million affected people worldwide. To this day, there are no existing therapies for the effective prevention or treatment of the disease. Many recently identified Alzheimer's disease-associated risk genes are expressed preferentially or exclusively in microglia, the immune cells of the brain. A recent study investigated the role of the microglia-specific Plcg2-P522R genetic variant in Alzheimer's disease and found that it enhances several immune cell-specific functions.

A genome-wide association study from 2017, which included a Finnish cohort of Alzheimer's disease patients and healthy controls, identified Alzheimer's disease-associated risk loci in three genes, TREM2, ABI3, and PLCG2, which are mainly expressed in microglia. Several genetic variants of the TREM2 gene have been found to increase the risk for Alzheimer's disease. These TREM2 variants lead to a partial loss of function of the receptor and impair the activation of microglia. Consequently, the removal of β-amyloid, which accumulates in the brain during Alzheimer´s disease, is reduced. Recently, it has been shown that the phospholipase C gamma 2 (PLCγ2) enzyme is involved in the signaling pathway initiated by TREM2. The PLCG2-P522R variant reduces the risk of developing Alzheimer's disease, but its effects on immune cell functions have not been previously described.

"It is interesting how several Alzheimer's disease-associated risk genes affect microglial cell functions through the same signaling pathway. It shows that targeting this pathway and the cellular functions it regulates may have significant therapeutic potential in the future."

Link: https://www.uef.fi/en/article/a-genetic-variant-that-protects-against-alzheimers-disease-promotes-immune-cell-functions

Researchers here investigate the regulation of mechanisms governing restoration of cell function following DNA repair. They find that H3K4me2, an epigenetic modification of histone H3, is important, and suggest that this could be a target for slowing the impact of DNA damage on the progression of aging. It is interesting to read this work in the context of data from last year that indicates detrimental epigenetic change with age may be an unfortunate side-effect of the repair process for double-strand breaks in DNA. It seems likely that, in the years ahead, an arm of the longevity industry will arise focused on manipulating DNA repair and surrounding mechanisms via known points of regulation such as histone H3.

The genome in every human cell is damaged on a daily basis, for example in the skin by UV radiation from the sun. Damage to the DNA causes diseases such as cancer, influences development, and accelerates aging. Congenital malfunctions in DNA repair can lead to extremely accelerated aging in rare hereditary diseases. Therefore, preservation and reconstruction processes are particularly important to ensure development and to maintain tissue function. DNA is rolled up into structures called chromatin, wound around the histone packaging proteins like cables on cable drums. This packaging is regulated by methyl groups. Various proteins are responsible for placing methyl groups on histones or removing them. The number of groups on the packaging proteins affects the activity of genes and thus the protein production of the cell.

In experiments with nematodes, the research team showed that after repairing damaged DNA, two methyl groups were increasingly found on the DNA packages. Furthermore, they found that errors in placing these two methyl groups on the histones (H3K4me2) accelerated the damage-induced aging process, while increased position of this histone alteration prolongs the lifespan after DNA damage. By controlling the proteins that either set or remove these methyl groups, the resistance to DNA damage - and thus the aging process of the animals - could be influenced.

Further analysis of the role of these two methyl groups showed that the enrichment of H3K4 after genome damage with two methyl groups supports the cells in restoring the balance after DNA damage. "Now that we know the exact changes in chromatin, we can use this to precisely limit the consequences of DNA damage. I hope that these findings will enable us to develop therapies for hereditary diseases characterized by developmental disorders and premature aging. Due to the fundamental importance of DNA damage in the aging process, such approaches could also counteract normal aging and prevent age-related diseases."

Link: https://portal.uni-koeln.de/en/universitaet/aktuell/press-releases/single-news/forschungsteam-entdeckt-mechanismus-der-die-zellfunktion-nach-genomschaeden-wiederherstellt

Mitochondria are the power plants of the cell, packaging the chemical energy store molecule adenosine triphosphate that is used to power cellular processes. NAD+ is important to mitochondrial function, but levels fall with age for reasons that have yet to be fully explored. The outcome is less efficient mitochondria, a decline that is implicated in the onset and progression of numerous age-related diseases. Reduced mitochondrial function means less functional cells, tissues, and organs, and particularly so in energy-hungry parts of the body such as the brain and muscles.

The research and development community has become increasingly interested in ways to boost NAD+ levels in order produce benefits to metabolism and tissue function in older individuals. So far, supplements based on vitamin B3 derivatives are the most studied approach, with results in old people that appear to be in the same ballpark as those produced by structured exercise programs. Combining those two approaches might be better still, but there is no evidence as yet as to whether or not that is the case, and these are still not radical reversals of the impact of aging. We all understand the bounds of the possible when it comes to what exercise can do for an older individual. It might be technically rejuvenation, in some ways, but only mildly so.

Can the medical community do better by identifying and targeting the deeper causes of NAD+ decline? In today's research materials, scientists demonstrate that at least some of this decline is due to the chronic inflammation that is characteristic of aging. They specifically call out the inflammatory signaling generated by senescent cells as a contributing cause, and reinforce the known link between CD38 expression and loss of NAD+. This is great work, and exactly the sort of thing we'd like to see more of in the future, strengthening the connections between known deeper causes of aging and known manifestations of aging, and thus bolstering the case for targeting those deeper causes in order to effectively treat aging.

Chronic inflammation causes a reduction in NAD+

NAD+ (nicotinamide adenine dinucleotide), a key metabolite central to an efficient and healthy metabolism, declines with age. This previously unexplained phenomena is associated with numerous age-related diseases and has spawned the development of many nutritional supplements aimed at restoring NAD+ to more youthful levels. Researchers have now identified chronic inflammation as a driver of NAD+ decline. They show that an increasing burden of senescent cells, which is also implicated in the aging process, causes the degradation of NAD via the activation of CD38 (cyclic ADP ribose hydrolase) a protein that is found on the cell membranes both inside and on the surface of many immune cells.

Experiments were done in mice and involved metabolic tissue from visceral white fat and the liver which were examined during aging and acute responses to inflammation. The work was validated in primary human macrophages. "Our initial hypothesis was that CD38 activation would be driven by inflammation. But we found that in this case, the activation occurred with both acute and age-related inflammation. That was a surprise."

Senescent cells, which stop dividing in response to DNA damage, spew a multitude of pro-inflammatory proteins, called the senescence-associated secretory phenotype or SASP. Evolution selected cellular senescence as a protective measure against cancer; but as senescent cells accumulate in tissues over the course of a lifetime, the SASP drives low grade chronic inflammation which is associated with age-related disease, including late life cancer. "These inflammatory proteins in the SASP induce macrophages to proliferate, express CD38, and degrade NAD+. It's a maladaptive process. But drugs that target the SASP or CD38 may offer us another way to deal with the decline of NAD+."

Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages

Declining tissue nicotinamide adenine dinucleotide (NAD) levels are linked to ageing and its associated diseases. However, the mechanism for this decline is unclear. Here, we show that pro-inflammatory M1-like macrophages, but not naive or M2 macrophages, accumulate in metabolic tissues, including visceral white adipose tissue and liver, during ageing and acute responses to inflammation. These M1-like macrophages express high levels of the NAD-consuming enzyme CD38 and have enhanced CD38-dependent NADase activity, thereby reducing tissue NAD levels.

We also find that senescent cells progressively accumulate in visceral white adipose tissue and liver during ageing and that inflammatory cytokines secreted by senescent cells (the senescence-associated secretory phenotype, SASP) induce macrophages to proliferate and express CD38. These results uncover a new causal link among resident tissue macrophages, cellular senescence, and tissue NAD decline during ageing and offer novel therapeutic opportunities to maintain NAD levels during ageing.

Stem cell activity declines with age, due in part to damage to these cells and their niches, but perhaps to a greater degree due to changes in the signaling environment resulting from rising levels of molecular damage and consequent dysfunction throughout the body. Not all of these signaling changes are obviously harmful; some are attempts to compensate. Some of those attempts produce benefits, slowing the overall pace of decline, but also unwanted side-effects. Researchers here note that the contents of extracellular vesicles released by cells change with age, and that hematopoietic stem cells react to vesicles from older individuals with signs of increased activity. This may compensate in part for a trajectory of declining integrity and activity, but it may also contribute to the risk of cancers and other immune dysfunction arising from the clonal expansion of mutations in hematopoietic cell populations.

Hematopoietic stem cells (HSCs) maintain balanced blood cell production in a process called hematopoiesis. As humans age, their HSCs acquire mutations that allow some HSCs to disproportionately contribute to normal blood production. This process, known as age-related clonal hematopoiesis, predisposes certain individuals to cancer, cardiovascular, and pulmonary pathologies. There is a growing body of evidence suggesting that factors outside cells, such as extracellular vesicles (EVs), contribute to the disruption of stem cell homeostasis during aging.

The present study demonstrates that healthy individuals maintain circulating EVs consistent in terms of size, particle concentration, and total protein per particle between 20-85 years of age. In contrast, blood EV protein profile composition changes over time in humans, and our in silico analyses, suggests that certain organs or cell types may be responsible for this change, by altering EV production and releasing EVs into the bloodstream. Most strikingly, the blood circulating EVs produced from middle and older-aged individuals stimulate HSC colony-forming ability in contrast to younger individuals and untreated controls.

This work highlights that blood EVs impart important extracellular signals to HSCs as humans age. We posit that EVs may provide a compensatory stimulus that counter-balances a decrease in HSC functionality in individuals approaching middle-age. Current work is investigating how these activation signals, provided by the EVs, may impact the trajectory of expansion of mutations via clonal hematopoiesis, which may have profound implications in the development of hematological-based malignancies later in life. We demonstrate, for the first time a fundamental age-specific difference in blood EVs that specifically affects HSCs in individuals after 40 years of age, prior to the detection of classically defined clonal hematopoiesis.

Link: https://doi.org/10.1111/acel.13245

Aggregation of phosphorylated tau protein into neurofibrillary tangles (and consequent toxicity leading to widespread cell death) is characteristic of late stage Alzheimer's disease, while dysfunction of the blood-brain barrier is a feature of aging thought to begin much earlier in the progression of the condition. The blood-brain barrier is a specialized set of cells lining the blood vessels of the central nervous system, allowing only certain molecules and cells to pass. When this barrier starts to leak, unwanted materials make their way into the brain, generating chronic inflammation and consequent issues in brain tissue. It is interesting to see discussion of potential effects of tau aggregation on blood-brain barrier leakage, as it wouldn't be the first significant causative mechanism that came to mind, given that tau is late and blood-brain barrier dysfunction is early in Alzheimer's disease. One could argue that tau aggregation and blood-brain barrier dysfunction are both downstream of chronic inflammation, while still being the case that both cause further chronic inflammation.

The blood-brain barrier (BBB) plays a crucial role in maintaining the specialized microenvironment of the central nervous system (CNS). In aging, the stability of the BBB declines and the permeability increases. The list of CNS pathologies involving BBB dysfunction is growing. The opening of the BBB and subsequent infiltration of serum components to the brain can lead to a host of processes resulting in progressive synaptic, neuronal dysfunction, and detrimental neuroinflammatory changes. Such processes have been implicated in different diseases, including vascular dementia, stroke, Alzheimer's disease (AD), Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, hypoxia, ischemia, and diabetes mellitus.

The BBB damage is also observed in tauopathies that lack amyloid-β overproduction, suggesting a role for tau in BBB damage. Tauopathies represent a heterogeneous group of around 20 different neurodegenerative diseases characterized by abnormal deposition of microtubule-associated protein tau (MAPT) in cells of the nervous system. Neuropathology of tauopathies is defined as intracellular accumulation of neurofibrillary tangles (NFTs) consisting of aggregated hyper- and abnormal phosphorylation of tau protein and neuroinflammation.

Disruption of the BBB found in tauopathies is driven by chronic neuroinflammation. Production of pro-inflammatory signaling molecules such as cytokines, chemokines, and adhesion molecules by glial cells, neurons, and endothelial cells determine the integrity of the BBB and migration of immune cells into the brain. The inflammatory processes promote structural changes in capillaries such as fragmentation, thickening, atrophy of pericytes, accumulation of laminin in the basement membrane, and increased permeability of blood vessels to plasma proteins. Here, we summarize the knowledge about the role of tau protein in BBB structural and functional changes.

Link: https://doi.org/10.3389/fnmol.2020.570045

This past week was Longevity Week in London, a yearly collection of events hosted by Jim Mellon's associates and allies that, this year, was held online given the present restrictions on gathering that continue to enacted in response to COVID-19. As is the case for near all infectious disease, this pandemic falls most heavily on the old and the frail. Perhaps understandably COVID-19 was a primary theme in the Longevity Forum discussions, now posted online.

The Longevity Forum itself is less focused on the science of aging and more focused on society, policy, and funding the scientific and medical development that will be needed to bring rejuvenation therapies into widespread use. There were still scientific discussions taking place in the broader context of Longevity Week, and I participated in one of the panels hosted by the Master Investor organization. We touched on the overlap between the science of aging and investment in clinical translation of that science in order to effectively treat aging as a medical condition. Both of Master Investor panel discussions are now published online, and you might take a look at those and other events from the recent Longevity Week.

Investing in the Age of Longevity 2020 | The Science of Ageing

We are on the cusp of a revolution in our understanding of the causes and consequences of aging. As aging research gathers pace, this panel discussion brings together some of the leading experts in the field of gerontology to discuss the cutting edge scientific work being done to advance the fight against aging.

Investing in the Age of Longevity 2020 | The Opportunity for Investors

The progress being made in extending life- and health-spans represents both a challenge and an opportunity. How can we ensure our investments see us comfortably through an extended life and how can we capitalise on the huge financial possibilities that successful treatments for aging would present? This panel brings together three of the leading investors in the field of Longevity to discuss the opportunities and potential pitfalls.

Researchers here note a correlation between greater exercise in late life and reduced risk of progressing from mild cognitive impairment to dementia. As is the case for most human data, causation cannot be shown, but animal data on the benefits of exercise are unambiguous. It seems safe to suggest that human physiology works much the same way, and that the correlation exists because exercise provides benefits that slow down processes of age-related neurodegeneration.

Physical activity has been suggested to prevent the conversion of mild cognitive impairment (MCI) to dementia in patients. We investigated the association between the continuance and regularity of physical activity and the risk of developing dementia in patients with MCI. We analyzed 6-year followed up data for 247,149 individuals in the National Health Insurance Service (NHIS) cohort of Korea who were enrolled between January 1, 2009, and December 31, 2015.

The patients were divided into four groups: those who did not engage in physical activity consistently (Never-PA group), those who initiated physical activity (Initiation-PA group), those who ceased physical activity (Withdrawal-PA group), and those who performed physical activity consistently (Maintenance-PA group). We also divided the patients into two groups: those who engaged in physical activity irregularly (Irregular-PA) and those who undertook physical activity regularly (Regular-PA).

Our analysis shows that continued physical activity in patients with MCI is associated with a lower risk of dementia of the Alzheimer type (DAT). It appears that the decision to start physical activity leads to a lower risk of DAT, while ceasing physical activity may cause the risk of DAT to increase again. In addition, a higher frequency of physical activity appears to prevent conversion from MCI to DAT (moderate-intensity physical activity more than 5 days per week or vigorous-intensity physical activity more than 3 days per week).

We observed that the Maintenance-PA group had 18% fewer dementia conversions than the Never-PA group, while the Initiation-PA group had 11% less dementia conversion than the Never-PA group. We interpret this to indicate that continuing physical activity occurring at both time points was more effective than initiating a new physical activity between the two time points. Evidence suggests that the longer the duration of physical activity, the greater the effect of physical activity on cognitive function. The findings for the Initiation-PA group may therefore reflect the shorter duration of physical activity compared to the Maintenance-PA group.

There are at least two major mechanisms by which continuous physical activity may prevent the conversion from mild cognitive impairment to dementia. Physical activity increases the expression of neurotrophic factors such as brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), and vascular endothelial growth factor (VEGF). BDNF is important for maintaining neuronal development and for exercise-related improvements in cognitive function. IGF-1 and VFGF play important roles in neurogenesis and angiogenesis and influence the induction of hippocampal BDNF.

Physical activity also increases cerebral blood flow (CBF). After 12 weeks of physical activity, CBF has been shown to increase in the anterior cingulate cortex and hippocampal CBF increased in elderly patients with subjective memory complaints after 16 weeks of physical activity. CBF is thought to maintain cerebral perfusion to help maintain brain volume.

Link: https://doi.org/10.1186/s13195-020-00707-1

The approach of lowering blood cholesterol via statins and similar medications slows the onset of atherosclerosis and consequent stroke and heart attack, but it isn't anywhere near as large an effect as we would like. This class of therapy isn't a cure and cannot be a cure, in the sense of removing existing atherosclerotic lesions, the fatty deposits that catastrophically weaken and narrow blood vessels. The latest approaches, such as PCSK9 inhibitors, can in the extreme case lower blood cholesterol to as little as 10% of human normal, but the outcome is still only a minor reversal of existing lesions. Some benefit is better than no benefit, and blood cholesterol lowering medications have changed the shape of late life human mortality for the better, but this approach of lowered blood cholesterol is not the right direction for the future of this field.

An observational study suggests that among people who have not had a previous cardiovascular event, those aged 70 to 100 years may gain the most benefit from taking medications that lower cholesterol compared to younger age groups, in terms of the number of heart attacks and cardiovascular events that could potentially be prevented per person treated. The study, involving more than 90,000 people living in Copenhagen, Denmark, including 13,779 people aged between 70 and 100 years, concluded that people aged over 70 years had the highest incidence of heart attack and cardiovascular disease of any age group. Heart attacks per 1,000 people per year irrespective of LDL cholesterol levels: Age 80-100, 8.5; age 70-79, 5.2; age 60-69, 2.5; age 50-59, 1.8; age 20-49, 0.8 - i.e. in people aged 80-100 years, there were 8.5 heart attacks per 1,000 people each year.

The study also estimates that the number of older people who need to receive a moderate-intensity statin therapy to prevent one heart attack in five years is fewer than for younger age groups. One heart attack will be prevented for every 80 people aged 80 to 100 years treated. In people aged 50 to 59 years, 439 need to be treated to prevent one incidence of heart attack, the researchers estimate.

In a separate systematic review and meta-analysis, researchers show that cholesterol-lowering therapies are as effective at reducing cardiovascular events in people aged 75 years or older as they are in younger people. The study, which included data from more than 21,000 people aged 75 years or older from 29 randomised controlled trials, found that cholesterol-lowering medications reduced the relative risk of major vascular events in older patients by 26% per 1mmol/L reduction in LDL cholesterol, which is comparable to the risk reduction in patients younger than 75 years (15% per 1mmol/L reduction in LDL cholesterol).

Together, the findings strengthen evidence that cholesterol-lowering medications can benefit older adults, who have historically been underrepresented in clinical trials of these therapies, and could help reduce the burden of cardiovascular disease in an aging population.

Link: https://www.eurekalert.org/pub_releases/2020-11/tl-pss110920.php

Today's article is a cut above the usual popular science standard in terms of detail and accuracy, capturing a snapshot of the present development of senolytic therapies. It is lengthy and touches on a range of present initiatives, companies, research programs, and clinical trials. Senolytics are one of the most important developments to emerge from the medical research community in quite a long time, in that they are the first rejuvenation therapy worthy of that classification. A senolytic treatment is one that selectively destroys senescent cells. These cells accumulate in old tissues, and while never rising to very large numbers, nonetheless contribute meaningfully to chronic inflammation and cell and tissue dysfunction of aging through the senescence-associated secretory phenotype (SASP).

Researchers have robustly and repeatably achieved rejuvenation in animal models via the use of senolytics, meaning reversal of measures of numerous age-related diseases, and extension of life span. Near any senolytic approach works, so long as it can remove senescent cells while avoiding harmful side-effects. Senescent cell accumulation is clearly an important process in aging, and a comparatively easy target for therapies intended to produce rejuvenation in the old.

A small number of human trials of first generation senolytic drugs have taken place in the past couple of years, some complete and published, some not. The initial trial data has been a mix of promising where it involved the use of the dasatinib and quercetin combination as a senolytic therapy, and an abject failure in the case of UNITY Biotechnology's attempt at treating osteoarthritis with a localized senolytic drug. The charitable viewpoint is that they tested the hypothesis that local administration could work, and have now demonstrated that it doesn't, because senescent cells in the rest of the body are delivering the lion's share of inflammatory signaling. The less charitable viewpoint is that the UNITY principals made poor decisions about drug choice and trial design, and that those choices looked like poor decisions ahead of time.

A single trial failure can put a damper on an entire class of treatment, causing investors to pull back, but in this case it seems quite clear that the the UNITY Biotechnology trial was not a good test of senolytics in humans. It wasn't even a good test of the ability of senolytics to treat osteoarthritis, given what we know of how it was conducted. And meanwhile, senescent cells are clearly proven in animal studies to cause the condition. Given what we know of the similar biochemistry of cellular senescence in mice and humans, the role of senescent cells in inflammation, and the role of inflammation in age-related diseases, it would be quite astounding to find that humans did not benefit greatly from clearance of senescent cells, in much the same way as occurs in mice. This is a very exciting area of development, and a very exciting time for the field of rejuvenation research.

Send in the senolytics

Unity Biotechnology was one of the darlings of the nascent anti-aging biotech sector. In August, that idea took a hit when Unity announced that its lead drug candidate had failed to beat a placebo in reducing joint pain and stiffness, according to interim results from a trial of patients with osteoarthritis of the knee. The company's stock plunged more than 60% on the news, nearly one-third of Unity staff were laid off, and its experimental drug UBX0101 - the first novel 'senolytic' agent ever to enter clinical testing - was swiftly abandoned.

That setback threw a pall over the entire senolytic field. A research note cited "substantially greater risk to the senolytic hypothesis." However, other experts were more sanguine about a class effect, highlighting issues with trial design, study population and UBX0101 itself - a small-molecule inhibitor of MDM2 designed to boost the activity of the proapoptotic p53 protein - as possible explanations for study failure. In the meantime, more than two dozen other startups continue to pursue approaches to target senescent cells - strategies that range from cell destruction and containment to senescence prevention and even reversal. "There are lots of different ways to tackle this, and I think that the initial failure of Unity's first clinical trial shouldn't be a discouragement. The field is young, it's still early, and there's a lot left to be discovered and tried," says Tim Cash, CSO of Senolytic Therapeutics.

Like Unity, most of these startups drew inspiration from a 2011 paper and a follow-up report showing the promise of senescent cell clearance to protect against age-related organ deterioration in normal aging mice as well. "I refer to those mice as the mice that launched a thousand ships," says Matthew Scholz, cofounder and CEO of Oisín Biotechnologies, a senolytics-focused gene therapy company. When it comes to raising funds, many of those senolytic 'ships' have hit rocky waters in recent months. Because of the UBX0101 trial failure, some investors - already burned once by the hype that surrounded the ill-fated anti-aging company Sirtris Pharmaceuticals and fearing a repeat with companies such as Unity - have shied away from pouring additional money into the antisenescence drug market.

Yet industry insiders say the problem with Unity's trial had more to do with the specifics of that drug and its study protocol than with the strategy of senolysis writ large. "Of course, we've been anxiously following their progress through the clinic, and we're disappointed too," says Lewis Gruber, CEO and CSO of SIWA Therapeutics, a company developing an antibody drug directed against a type of advanced glycation end product found on the surface of senescent cells. "But the actual technical results are, at least so far, not of concern to us. We don't see it as a problem for senolytics in general."

For starters, MDM2 may not have been the best target for senescent cell destruction. The protein is one of the most important negative regulators of p53, responsible for the ubiquitination and degradation of the proapoptotic tumor suppressor. As such, inhibiting MDM2 risks unleashing indiscriminate cell killing in off-target, non-senescent tissues. To avoid that kind of toxicity, Unity relied on a local delivery strategy. But according to biomedical engineer Jennifer Elisseeff from Johns Hopkins University in Baltimore, Maryland, local injections of UBX0101 are not sufficient to improve knee function in old mice with osteoarthritis. In her lab, systemic administration of another senolytic agent, navitoclax, was needed to tamp down the general inflammation in the body that was hampering tissue repair.

Then there's the drug itself. Other senescence researchers say that, in their hands, MDM2 inhibitors such as nutlin-3a have only weak senolytic activity. And there's evidence from Judith Campisi's lab to suggest that the drug could also work through attenuation of the SASP. If that mechanism predominates over cell elimination, a single dose of UBX0101, as administered in the trial, might thus offer only temporary relief before the inflammatory secretome would come flaming back.

Yet the early success of dasatinib and quercetin in human trials at least shows that the concept of senolysis is possible in patients. And it gives anti-aging researchers hope that more pronounced benefits will be seen with therapeutics rationally designed to modulate senescence in some way. "It'll happen sooner or later. The technology is just too good."

Kimer Med is a New Zealand biotech startup in the very early stages of work on improvement and commercialization of the DRACO antiviral technology. This approach works by selectively destroying cells that host viral replication, and has been shown to be effective for a few presently challenging viral infections in animal models. In principle it is a platform extensible to any viral infection. Unfortunately DRACO fell into the usual chasm, made up of a lack of funding for later stage academic research, a lack of strong-willed iconoclasts willing to go to bat for it, and a lack of interest in the pharmaceutical industry for anything that isn't neatly packaged and ready to go.

The Kimer Med principals are providing the strong-willed iconoclast component of the mix, but there is work yet to do in order to attract investors: nailing down intellectual property, proving that replication and improvement of the original DRACO formulation works as they claim, and so forth. So the team is giving crowdfunding a try for their early development plan. This has long been a technology of interest for the longevity community for some years, as it might be a way to address herpesviruses like cytomegalovirus that appear to be important in the age-related decline of the immunity system. So take a look at the crowdfunding page, and give some though to helping out.

We are working on a broad-spectrum antiviral drug. You can help us achieve a future free of the suffering caused by viruses. SARS-CoV-2 is just the tip of the iceberg. We also plan to tackle HIV, Hepatitis B, Influenza, Herpes, CMV, EBV, the common cold, and others. Viruses infect animals, too, both pets and livestock. Today, almost a hundred years after the discovery of penicillin and sulfa, although we have a few antivirals, none of the current commercial products have a breadth of activity that even slightly measures up to the spectrum of those first antibiotics. In fact, new antivirals currently have to be customized for each different virus. For example, Tamiflu only works for the flu, not SARS-CoV-2, and viruses are already developing resistance.

However, a few years ago, researchers at MIT's Lincoln Lab came up with an antiviral protein that works much differently from conventional antiviral drugs. Their published research showed this compound to be effective against 15 different viruses, including Influenza H1N1, Rhinovirus (the common cold), Dengue, Adenovirus, and others - a true broad-spectrum antiviral. With the advent of Covid-19, as well as with the significant human, animal and financial burden of many other viruses, and the ongoing risk of the appearance of new ones, the time is right to pick up where Lincoln Lab left off, and complete the commercial development of this compound. We believe this protein is non-toxic and that it should also be effective against SARS-CoV-2. Based on the way it works, there is good reason to believe it could be effective against a very wide range of viruses.

The next step is funding for fabrication and testing, including against SARS-CoV-2. We've already done the legwork of identifying the suppliers we will need, and the costs and associated regulations. Most or all of this work can be contracted-out, so we don't even need a laboratory of our own yet. We are anticipating the need to fine-tune our fabrication process a bit, followed by additional testing in the lab, and then quickly moving on to in vivo testing. Once successful in lab animals, we plan to progress to safety trials in people. We want to make this drug safe and available for use in humans as soon as we practically can.

This compound's effectiveness has already been replicated and published by two other labs. In one, they tested against PRRSV. In the other, against Influenza. Previous lab testing shows that the compound has been effective against every virus tested, including a wide-cross section of virus types. However, unknowns do remain. This is why we need your help. In addition to confirming effectiveness, we want to look at things like dosing. As with most drugs, there may also end up being certain contraindications or limitations, which we will need to identify, and work around if we can.

Link: https://donate.kimermed.co.nz/campaign/2/ending-viral-disease

Fibrosis is a consequence of age-related disarray in tissue maintenance processes, leading to the deposition of scar-like collagen that disrupts tissue structure and function. It is an ultimately fatal issue for which there are only poor treatment options at present. Hopefully that will change with further exploration of the relationship between accumulation of senescent cells in aged tissues and the development of fibrosis. In mice, the use of senolytic therapies to selectively destroy senescent cells has reversed fibrosis in a number of different organs.

A substantial minority of participants from the Framingham Heart Study, (nearly nine percent), had potentially clinically significant liver fibrosis (scarring). This the first study of this size and scale done in the United States. More than 3,000 middle-aged Framingham Heart Study participants (over a three-year period) underwent a test or vibration-controlled transient elastography that quantifies how much fat is in the liver and also measures the stiffness of the liver. Liver stiffness correlates with the degree of liver scarring. "We found that liver fibrosis was associated with more adverse cardiometabolic risk factors, even after accounting for liver fat which is a known risk factor for cardiometabolic disease. In particular, we observed that approximately one-quarter of the participants with diabetes had evidence of possibly clinically significant liver fibrosis."

These findings support the consideration of screening for liver fibrosis in high-risk groups, though additional studies are needed to determine the benefits/costs of screening. "Liver biopsy is the gold standard for diagnosing liver fibrosis; however, new non-invasive tests exist that can quickly and painlessly help doctors determine if you are at risk for having clinically significant liver fibrosis." If liver fibrosis is identified early, before cirrhosis is established, it is treatable. Greater recognition of and awareness of liver fibrosis as a consequence of nonalcoholic fatty liver disease will hopefully allow more patients to receive treatment to prevent complications of advanced liver disease.

Link: https://www.eurekalert.org/pub_releases/2020-11/buso-lsr110920.php

The vascular system does not age gracefully. Blood vessel walls become stiff and inflamed, interfering in contraction and dilation in response to circumstances. The result is the raised blood pressure of hypertension, which causes damage throughout the body in numerous ways. Further, the fatty lesions of atherosclerosis form in later life, weakening and narrowing blood vessels. This is the result of increased levels of oxidized cholesterol molecules, causing the macrophages responsible for cleaning up blood vessel wall tissues to falter in their tasks. Further still, the blood-brain barrier that lines blood vessels in the brain breaks down and leaks unwanted cells and molecules into brain tissue, causing neuroinflammation and the onset of cognitive decline. But there is more than even this, such as the loss of capillary network density that leads to a declining supply of nutrients and oxygen to tissues throughout the body.

Today's short open access paper is a brief tour of a few strategies for which there is evidence for their application to reduce the impact of vascular aging. It is a mixed bag in terms of size of effect, reliability, and quality and amount of evidence. The best of the bunch is likely senolytic therapies that selectively destroy senescent cells, but even here, while the animal data is quite impressive, that outcome remains to be proven in human trials. The point to take away from this is that the aging of the vascular system is quite important in the progression of degenerative aging. A great many issues lie downstream of hypertension, blood-brain barrier dysfunction, and the other manifestations of vascular aging, and so successful interventions will be broadly beneficial.

Novel update of interventional strategies of vascular aging in humans

Classical strategies targeting mechanisms of vascular aging to delay vascular aging and prevent disease, such as exercise, diet, and other lifestyle interventions, have far-reaching significance. However, these alone seem to be insufficient to prevent the occurrence of geriatric disease and efforts are needed to tackle the underlying processes of vascular aging. At present, the most promising novel strategies for delaying vascular aging include improving the function of mitochondria, reducing age-related inflammation, increasing autophagy, moderately reducing the activity of the nutrient-sensing network, especially reducing the activity of mammalian target of rapamycin complex 1 (mTORC1), removing senescent cells, and using its own endogenous metabolites to re-energize stem cells, and so forth. Several potential drugs and natural products have been reported to modulate aging. Shedding light on the mechanisms of vascular aging and the development of novel agents will likely reduce the risk of age-related disease and extend the human health span.

Senolytics

Senolytics is a class of drugs that selectively kill senescent cells, and scientists have reported the first senolytics drug combination - dasatinib + quercetin. Recent studies demonstrated that senolytic treatment exerted a positive effect on senescent cell burden, DNA damage, vasomotor function, nitric oxide signaling, calcification, and osteogenic signaling in chronologically aged mice. Another study indicated that this combination selectively cleared senescent cells in idiopathic pulmonary fibrosis mice and improved lung function and physical health indicators in mice. In an open-labeled phase I clinical trial, nine patients with diabetic nephropathy received dasatinib and quercetin therapy, which reduced the load of adipose tissue senescent cells. The effect of senolytic treatment may be mediated by members of the BCL-2 family, PI3K/AKT, p53/FOXO4, HSP90, and HIF1α. These results proved that senolytics are expected to be used to delay vascular aging and prolong the life span of the elderly.

Metformin

Metformin is a biguanide drug widely used for type 2 diabetes. A study on mice found that treatment with metformin mimics some of the benefits of calorie restriction, such as increased insulin sensitivity and reduced low-density lipoprotein and cholesterol levels and finally improves health span and life span. Retrospective, epidemiological analyses elucidated that administration of metformin is associated with the improvement of vascular function and reductions in the incidence and mortality of ischemic disease. The results of metformin treatment in age-related disease are also encouraging, with a wide range of protective roles in cardiovascular disease, cerebrovascular disease, cancer, chronic kidney disease, and neurodegeneration.

Rapamycin

Studies showed that rapamycin destabilizes and inhibits mTORC1, which is an important molecule regulating various cellular processes. It was proposed that rapamycin extended the life span by up to 60% and even reversed the changes in vascular function and structure, cognition, cardiac hypertrophy, and immune senescence in aged mice, through both genetic and pharmacological modulation of mTOR signaling. The current clinical uses of rapamycin may be limited by its adverse effect to some extent, including hyperglycemia and hyperlipidaemia. As an effective anti-vascular aging agent, rapamycin has both advantages and disadvantages and it should be balanced for every individual.

Nicotinamide adenine dinucleotide and sirtuins

Nicotinamide adenine dinucleotide (NAD+), as a cofactor in many key biological processes of cells, is an important mediator of biochemical reactions in the body and an essential molecule in many metabolic pathways. It has been found that the concentration of NAD+ in human tissues gradually decreases with age, and at least decreases by 50%, accompanied by a series of pathological processes, such as chronic inflammation, oxidative stress, DNA damage, and mitochondrial dysfunction. Supplementation of NAD+ and its precursors is beneficial to reduce the occurrence of oxidative stress, increase the regenerative capacity of vascular endothelial cells, and prolong cell life.

Berberine

Berberine is an isoquinoline alkaloid extracted from various plants, which plays an important role in lowering blood pressure, regulating blood lipids, and controlling blood glucose. It was found that berberine could activate the AMPK-signaling pathway, and inhibit the activity of mTOR to delay cell senescence caused by DNA replication disorder, and also increase antioxidant activity by activating the NRF2-signaling pathway to achieve the effect of longevity extension.

Nucleoside reverse transcriptase inhibitors

Nucleoside reverse transcriptase inhibitors (NRTIs) are used in clinical HIV treatment, but can also inhibit open-reading frame-related reverse transcriptase activity of long dispersive elements. Recent studies have found that NRTIs, including lamivudine and stavudine, can reduce senescence-related secretory phenotypes and inflammatory responses in older mice. These findings make NRTIs a new candidate for delaying aging.

Remote ischemic preconditioning

Remote ischemic preconditioning (RIPC) is a safe, noninvasive, simple, and low-cost non-drug device intervention and has been widely used since it was first proposed. RIPC is an intrinsic protective phenomenon to protect the vital organs with non-fatal regional ischemia followed by reperfusion, through the involvement of SDF-1α, HIF-1α, oxidative stress, and apoptotic pathways. A recent study has demonstrated that 1-month RIPC treatment can significantly reduce the blood pressure of patients with mild essential hypertension and improve microvascular endothelial function.

This article considers one newer venture fund that is focused on the growing longevity industry. It is far from the only such recently created fund; one might consider SP8CEVC and Longevitytech.fund as other examples. There are more. Biotech startups attempting to address mechanisms of aging are launched at a faster rate these days, and an increasing amount of capital is coming into the space. These are still the early years for this industry, but the trend is apparent. The thesis that one can intervene in the aging process to productively slow or reverse aging is going to be solidly tested in practice in the years ahead.

Not long after Deep Longevity, Inc was acquired by Regent Pacific, funding details have been revealed. First early-stage investment fund LongeVC is using this latest exit to create its first early-stage investment fund, which will be focused on biotech and Longevity opportunities. Deep Longevity closed a Series A funding round at the end of June 2020. LongeVC was joined in the round by some of the most worldwide well-known venture capitalists specialising in biotechnology, Longevity and AI, including ETP Ventures, Human Longevity and Performance Impact Venture Fund (the corporate venture arm of Human Longevity, Inc.), BOLD Capital Partners, Longevity Vision Fund, Oculus co-founder Michael Antonov, as well as other AI and biotechnology investors.

LongeVC is an investment group, specialising in curating, facilitating and executing early-stage venture investments in the fields of biotech and Longevity. Its current investment portfolio includes Insilico Medicine, a global leader in AI-driven drug discovery and Longenesis, an end-to-end collaborative biotech research enabler, as well as other biotech industry-specific companies.

Addressing the Regent Pacific acquisition of Deep Longevity and his fund's exit, LongeVC Partner Sergey Jakimov told us: "Our team welcomes this acquisition and is proud to have participated in one of the testimonies to the enormous future potential that the longevity industry has to offer. It is a unique deal for the Baltic area, and we are determined to use our expertise to screen and invest in similar deals globally." Currently the new fund LongeVC is being set up, with the total amount of the money available from the fund estimated to be $35m. "We are targeting seed-stage and pre-A funding round companies as there are limited opportunities worldwide to get investments at these stages."

Link: https://www.longevity.technology/longevc-launches-new-35m-longevity-investment-fund/

Nerves regenerate poorly, and the regrowth of axons linking neurons following injury is hampered by scar formation. Finding a way to force greater regrowth of nerve tissue is an important goal for the regenerative medicine community. A variety of methods have shown some promise in early stage studies, and the example here is one among many. There has to date been comparatively little progress towards the clinic, however.

Glaucoma is a disease caused by progressive damage to the optic nerve, which transfers visual information from the eye to the brain. Conventional treatments focus on reducing eye pressure to prevent optic nerve damage, but they do not work for about 15 per cent of patients and there is currently no way to repair damaged nerve cells.

Researchers tested whether a gene responsible for producing a protein known as protrudin could stimulate the regeneration of nerve cells and stop them from dying when they were injured. They used a cell culture system to grow brain cells in the lab and then injured them using a laser before introducing a gene to increase the amount of protrudin in the cells, vastly increasing their ability to repair and regenerate.

Tests of eye and optic nerve cells found the protein enabled significant regeneration weeks after a crush injury to the optic nerve. The research demonstrated almost complete protection of nerve cells from a mouse retina growing in cell culture, a technique which would usually be expected to result in extensive cell death. Next steps are to explore the ability of protrudin to protect and regenerate human retinal cells.

Link: https://www.cera.org.au/gene-therapy-research-regenerates-optic-nerve-bringing-hope-for-future-glaucoma-treatment/

Not every SARS-CoV-2 infection in the COVID-19 pandemic is equal. Young people near all shrug off infection with a few weeks of inconvenience at worst. Old people, on the other hand, exhibit more significant illness and a high mortality rate. That mortality rate increases with both advancing age and the presence of inflammatory age-related chronic disease. The average 20 year old has a radically different risk profile when compared to the average 80 year old. This is one of the reasons why the commonly presented data, estimated infections per capita, or detected infections over time, is unhelpful. It needs the context of the age of the patients.

The popular media shows no inclination to correctly present SARS-CoV-2 as being a meaningful threat only to older people, tending to focus on overall infection counts, as well as on the tiny number of young people who are greatly impacted or killed by SARS-CoV-2. Meanwhile, the scientific community continues to publish papers that state the obvious on this topic. Viral infection disproportionately harms old people because of immunosenescence and inflammaging, the age-related decline in immune system competence and function. The best way to address the problem of mortality due to infectious disease in the elderly is to build therapies that can restore immune function.

There are many plausible approaches to improved immune function in the old. Regrowing the thymus. Improving hematopoietic stem cell function. Clearing out malfunctioning or damaged populations of immune cells. Regenerating fibrotic lymph nodes. A great deal more funding and effort should be directed towards these goals than is presently the case.

Aging in COVID-19: Vulnerability, immunity and intervention

The majority of COVID-19 cases are mild. Some people may not have any clinical manifestation at all after SARS-CoV-2 infection. These asymptomatic individuals can serve as a source of virus spread. A report of the data in New York State up to March 31, 2020 showed that 47,326 persons out of 141,495 were tested positive (33%) for COVID-19, and many of those positives were asymptomatic. However, more surveillance data are needed to evaluate the extent of asymptomatic infection. In an infectious disease as heterogeneous as COVID-19, host factors are the key to determine disease severity and progression. For severe COVID-19 disease, major risk factors include age, male sex, obesity, smoking, and comorbid chronic conditions such as hypertension, type 2 diabetes mellitus, and others. Overwhelming evidence from around the world suggests that age itself is the most significant risk factor for severe COVID-19 disease and its adverse health outcomes.

Early data from China demonstrate that case fatality ratio (CFR) of COVID-19 increases with age, from 0.4% or lower in patients aged in the 40s or younger, 1.3% among those in their 50s, 3.6% in their 60s, 8% in their 70s, to 14.8% in their 80s or older; the overall CFR is 2.3%. In comparison, the overall CFR was approximately 2.8% worldwide and 2.7% in the US as of October 19, 2020. A more profound effect of aging is shown by COVID-19 CFR data from Italy, the first country affected by the pandemic after China. Again, CFRs are from less than 0.4% or lower in patients aged in the 40s or younger, 1% among those in their 50s, 3.5% in their 60s, 12.8% in their 70s, to 20.2% in their 80s and above; the overall CFR is 7.2%. Of note, the overall CFR is higher in Italy than that in China (7.2% vs 2.3%, respectively). This is likely because Italy not only has a higher CFR than China among adults over 70 years of age, but also has a higher proportion of older adults than China (22.8% vs 11.9%, respectively).

Data reported by the US Center for Disease Control and Prevention (CDC) also demonstrate significantly higher rates of hospitalizations, ICU admissions, and deaths secondary to COVID-19 among older adults (older then 65 years) than any younger age groups. Perhaps, the most striking evidence is the data on COVID-19 cases and death in nursing homes across the US. Currently, there are up to 1.5 million nursing home residents in the US, less than 0.5% of its population. However, about 7% of confirmed COVID-19 cases were among these vulnerable elderly individuals. Moreover, they suffered 40% of COVID deaths in the US. Taken together, it is unmistakable that aging is an important risk factor for severe COVID-19 disease and its adverse health outcomes including hospitalization, ICU admission, and death.

Many research groups are using the extensive data that can be gathered on protein levels, transcription, or epigenetic marks in order to construct clocks that measure the impact of aging on an individual. All of this data changes from moment to moment and from year to year, alongside health, environment, and the biological damage of aging. Accuracy in terms of correlation with chronological or biological age varies widely, but at a few of the clocks are quite good in this regard. The work here is one example of many similar projects presently underway, in which data is sifted in search of protein levels that change in characteristic ways with age.

The present study identified proteomic profiles associated with chronological age and proteomic signatures related to aging phenotypes in a unique population of older adults. Maintenance of homeostasis is important in successful aging, whereas major deviations from stable physiology that can be captured by changes in the proteome may reflect accelerated aging and disease prevalence. Our findings demonstrated that individuals with a family history of longevity exhibit a proteome that is suggestive of delayed aging. Additionally, we showed that clusters of proteins, which were associated with age, were also related to complex diseases and other age-associated phenotypes.

We hypothesized that the proteome can capture the biology underlying the physiological age and not simply the chronological age. We tested this hypothesis in a homogenous community-dwelling cohort of Ashkenazi Jewish older adults in whom ~4,265 plasma proteins were measured. As part of the study, we aimed to develop an age prediction model based on the proteome and to test whether it predicted mortality. In addition, our cohort was enriched with individuals with familial longevity, with approximately half of the cohort composed of offspring of parents with exceptional longevity who repeatedly demonstrated better health status compared to age-matched controls

In the 1,025 participants of the LonGenity cohort (age range: 65-95, 55.7% females), we found that 754 of 4,265 proteins were associated with chronological age. Pleiotrophin (PTN), WNT1-inducible-signaling pathway protein 2 (WISP-2), chordin-like protein 1 (CRDL1), transgelin (TAGL), and R-spondin-1(RSPO1), were the proteins most significantly associated with age. Weighted gene co-expression network analysis identified two of nine modules (clusters of highly correlated proteins) to be significantly associated with chronological age and demonstrated that the biology of aging overlapped with complex age-associated diseases and other age-related traits. Pathway analysis showed that inflammatory response, organismal injury and abnormalities, cell and organismal survival, and death pathways were associated with aging.

Link: https://doi.org/10.1111/acel.13250

The microbes of the human gut change with age, losing beneficial populations that promote tissue function throughout the body via the metabolites they generate, and gaining harmful populations that generate chronic inflammation and tissue dysfunction. The causes of this problem are varied and still under investigation, but it seems very plausible that methods of reversing the age-related alterations in microbial populations can be established. For example, fecal microbiota transplantation has been shown to restore a youthful gut microbiome and extend life in killifish, and is already used in human medicine for conditions in which pathogenic bacteria have overtaken the intestine. Equally, it seems likely that some novel, tailored form of high dose probiotic therapy could achieve similar results.

Generally, the gut microbial communities in human are stable; however, they can be altered in the different conditions by the effects of various factors. Recently, the studies of several groups have been demonstrated that various diseases, including intestinal diseases and more systemic diseases such as diabetes, metabolic syndrome, and neurodegenerative disorders, including Alzheimer's disease (AD) and others, are related to the imbalance of gut microbiota called "dysbiosis". Occurrence and development of AD and other neurodegenerative disorders may be accompanied by the gut microbiome dysbiosis, inflammation, and dysfunction of the gut-brain axis. It has been speculated that AD may appear during the aging of immune system based on the theory of age-related dysbiosis derived from the association between gut microbiota and AD, which has been evidenced by clinical and experimental studies.

Generally, the traditional ecological measures are used to characterize the composition of the gut microbiome, including richness (the number of unique operational taxonomic units, OTUs, present in a participant), alpha diversity (the richness and abundance of OTUs within each participant), and beta diversity (the similarity or difference in composition between participants). Declined microbial richness and diversity as well as a distinct composition of the gut microbiome were found in AD patients. The levels of differentially abundant genera were correlated with cerebrospinal fluid (CSF) biomarkers of AD pathology. In short, definite genera as more abundant in AD were related to greater AD pathology, whereas genera as less abundant in AD were associated with less AD pathology.

There is also a close interaction between gut microbes and the local as well as systemic immune system. In general, the gut dysbiosis could lead to dysfunctions of both innate and adaptive immune through several ways, such as changing antigen presentations, cytokines production, and lymphocyte functions, as well as increasing inflammation, etc., also can cause the gut-brain axis malfunction. In AD patients, the molecular and cellular alterations involving immune cells, such as T cells, B cells, microglia, etc., as well as immune mediators, occur not only in the peripheral blood, but also in the brain and the CSF, which may be associated with triggering immune response by the gut dysbiosis. The gut dysbiosis impacts on innate and adaptive immune response in AD patients obviously via activating immune/inflammatory cells, shifting them into inflammatory type to enhance immune mediated inflammatory response, and promoting neurodegeneration in the brain. The gut dysbiosis in AD was obviously correlated with more T helper 1 (TH1) cell infiltration into the brain, and increased T-cell infiltration in the brain parenchyma and peripheral T-cell responses to amyloid-β have been found in AD patients.

Link: https://doi.org/10.3389/fnagi.2020.544235

Age is characterized by a growing degree of unprompted, unresolved inflammation. Inflammation is a rousing of the immune system into action, a necessary process that aids in the defense of the body against pathogens, as well as in regeneration of injuries. In youth, inflammation is near always promptly resolved once the need is passed. In old age, however, inflammation becomes constant, triggered by many distinct causes: persistent infections; metabolic waste; the breakdown of the intestinal barrier and the blood-brain barrier, leaking unwanted molecules, cells, and pathogens; and rising numbers of senescent cells that secrete inflammatory signals.

Constant, unresolved inflammation is disruptive of tissue maintenance and function throughout the body. In recent years, the research community has demonstrated quite conclusively that accumulation of senescent cells in old tissues causes a significant fraction of this chronic inflammation of aging. Targeted removal of as few as a third of the senescent cells present in tissue via senolytic therapies reduces inflammatory signaling and reverses many of its consequences. This has been amply demonstrated in mice, but human trials of first generation senolytic drugs have to date only assessed a few conditions and a few different approaches to destruction of senescent cells.

As noted in today's open access paper, inflammation and cellular senescence is important in the vascular stiffening and thickening of age, a process that contributes to hypertension and all of the major damage to tissues and systems in the body and brain then caused by chronically raised blood pressure. Interestingly, it is possible to link increased levels of cellular senescence in blood vessel walls with the presence of advanced glycation end-products (AGEs), sugary metabolic waste that forms cross-links between collagen and other molecules of the extracellular matrix, changing the structural properties of tissue as a result. Reduced elasticity (i.e. stiffening) is one direct consequence, but these changes also likely cause nearly cells to react in ways that increase the burden of cellular senescence in that tissue.

Proinflammation, profibrosis, and arterial aging

Aging is a major risk factor for the morbidity and mortality of quintessential cardiovascular diseases, such as hypertension and atherosclerosis, mainly due to arterial wall structural and functional adverse remodeling, such as intimal medial thickening (IMT) and stiffening. The age-associated increase in collagen deposition within the arterial wall is known as arterial profibrosis; and the age-associated increase in sterile inflammation within the wall is known as arterial proinflammation. Proinflammation and profibrosis are the key molecular and cellular events in age-associated IMT and arterial stiffening. It is widely accepted that proinflammatory endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) are mainly responsible for age-associated adverse arterial cellular events; however, the consequence of proinflammation and profibrosis (predisposing collagen deposition) greatly affects the behavior of these cells adversely with a predominant impact on the age-associated arterial stiffening, which is not completely understood.

In the aging arterial wall, collagen types I, II, and III are predominant, and are mainly produced by stiffened vascular smooth muscle cells (VSMCs) governed by proinflammatory signaling, leading to profibrosis. Profibrosis is regulated by an increase in the proinflammatory molecules angiotensin II, milk fat globule-EGF-VIII, and transforming growth factor-beta 1 (TGF-β1) signaling and a decrease in the vasorin signaling cascade. The release of these proinflammatory factors triggers the activation of matrix metalloproteinase type II (MMP-2) and activates profibrogenic TGF-β1 signaling, contributing to profibrosis. The age-associated increase in activated MMP-2 cleaves latent TGF-β and subsequently increases TGF-β1 activity leading to collagen deposition in the arterial wall.

Collagen fibrils become resistant to cleavage over time. Mice with a targeted mutation that yields collagenase-resistant type I collagen create an old senescent phenotype. VSMCs in the aortic wall of these mutated mice are susceptible to stress-induced cellular senescence, displaying senescence-associated beta-galactosidase (SA-β-Gal) activity and upregulated p16 in response to angiotensin II infusion. In addition, mutant collagen directly reduces the replicative lifespan of human VSMCs and increases stress-induced measures of cellular senescence such as SA-β-Gal activity, p16 expression, and p21 expression. Thus, resistance to collagen cleavage, such as advanced glycation endproduct (AGE) formation, accelerates cellular senescence, arterial stiffening, and aging. A long-term senolytic treatment (intermittently with dasatinib + quercetin via oral gavage) significantly eliminates senescent cells in the medial layer of aortae from aged mice and reduces arterial stiffening.

Senescent cell accumulation is an important feature of aging, both for its contribution to the chronic inflammation of old age, as well as the disruption of tissue function that leads to age-related disease. Targeting senescent cells for destruction via senolytic drugs is an area of clinical development that is growing in popularity, but it isn't the only possible approach. This paper is interesting for its taxonomy of drugs and other compounds that either selectively destroy senescent cells, prevent cells entering senescence, or mute portions of the senescence-associated secretory phenotype (SASP) that causes harm to surrounding cells and tissues. These strategies will likely turn out to be widely divergent in risk and outcome; selective destruction still appears the best of them to my eyes. But read the whole paper, as the summary below isn't the point of it, but rather the list and categorization it provides.

Aging leads to a high burden on society, both medically and economically. Cellular senescence plays an essential role in the initiation of aging and age-related diseases. Recent studies have highlighted the therapeutic value of senescent cell deletion in natural aging and many age-related disorders. However, the therapeutic strategies for manipulating cellular senescence are still at an early stage of development. Among these strategies, therapeutic drugs that target cellular senescence are arguably the most highly anticipated. Many recent studies have demonstrated that a variety of drugs exhibit healthy aging effects.

Senolytics are agents that selectively induce the apoptosis of senescent cells. This type of drug can be classified into BCL family inhibitors, PI3K/AKT inhibitors, and FOXO regulators. The BCL family is composed of pro-apoptotic proteins and pro-survival proteins. The PI3K/AKT pathway is one of the pro-survival pathways in senescent cells. Studies have shown that phosphoinositide 3-kinase (PI3K) is involved in protecting cells against apoptosis. FOXOs controls cell functions such as growth, survival, metabolism, and oxidative stress. Studies have shown that FOXO4 can interact with p53, inhibit p53-mediated apoptosis, and thus maintain the vitality of senescent cells.

Another major feature of senescent cells is the acquisition of SASP. Drugs that target SASP, such as antioxidants, Wnt/β-catenin inhibitors, and Janus kinase (JAK) inhibitors, also have healthy aging effects since SASP is associated with a pro-inflammatory status and a faster aging rate.

Link: https://doi.org/10.1177/2040622320964125

In multiple sclerosis, the immune system becomes intolerant towards myelin, the sheathing around nerves that is essential to nervous system function. One class of approach to treating autoimmune diseases of this nature is to produce immune tolerance by delivering more of the problem molecule into the body. The challenge in multiple sclerosis is that it is unclear as to which of the many possible protein sequences is the problem in any given patient, and indeed to build a comprehensive list of such sequences in the first place. Researchers here report on the discovery that the oligodendrocyte cells responsible for building and maintaining myelin sheathing secrete a wide variety of myelin antigens in extracellular vesicles. These vesicles are comparatively easy to harvest from cell cultures, and thus are a good potential basis for an immune tolerance therapy that could work for all multiple sclerosis patients.

Multiple sclerosis (MS) is an autoimmune disorder that develops as the body's immune system attacks the central nervous system. Specifically, it attacks the protective layer surrounding nerve cells, called the myelin sheath. Current MS therapies aim to counter this inflammatory response by suppressing the immune system, which can lead to serious side effects like a higher risk of infection, and even cancer. Researchers have found a way to prevent immune cells from attacking myelin and halt disease progression, while leaving the rest of the immune system intact, in mouse models of MS.

"There are many possible immune-activating antigens in the myelin sheath, but the biggest hurdle is that we don't know which component of myelin is triggering the immune response in MS patients. Previous studies have used single myelin antigens or combinations of antigens to prevent auto-immunity in animal models, but in humans they have had limited success." For answers, the researchers turned to cells called oligodendrocytes. These cells wrap their cell membrane around nerve cells to produce the myelin sheath. Tiny sacs called extracellular vesicles (EVs) can be harvested from cultured oligodendrocytes. The researchers found that these EVs contain almost all the relevant myelin antigens. With all of the antigens present, there'd be a higher chance that these vesicles could halt the autoimmune attack on myelin. "The neat thing about these EVs is that they give us an opportunity to treat the disease in an antigen-specific way, without having to know the exact identity of the target antigen. It covers all the bases."

The researchers were able to safely inject the EVs intravenously in three different mouse models of MS representing early and late stages of the disease. When administered before disease developed, the EVs had a prophylactic effect, preventing the onset of symptoms like decrease in mobility and paralysis. When given after disease onset, EVs significantly reduced severity of disease in all three models, to the point that the animals could walk again. "The antigens involved in the auto-immune response can differ between MS patients, and even change over time in an individual patient. The fact that our approach was effective in different experimental models shows this could act as a universal therapy."

Link: https://www.jefferson.edu/about/news-and-events/2020/11/a-novel-immunotherapy-proves-effective-in-animal-models-of-multiple-sclerosis.html

Cross-links that join together molecules of the extracellular matrix are necessary for the normal structural properties of tissue. Cross-links can also be formed in a detrimental way by advanced glycation endproducts (AGEs), a form of metabolic waste, and thereby impair structural properties of tissue. Most AGEs are short-lived, but some are quite persistent, hard for our biochemistry to break down, and build up with age. High levels of AGEs are characteristic of an abnormal metabolism, such as in diabetic patients, and can cause long-term harm by promoting inflammation and altered cellular behavior through the receptor for AGEs (RAGE).

Persistent cross-links formed by AGEs, rather than by normal tissue maintenance processes, can reduce elasticity in skin and blood vessels. Of interest to the authors of today's open access research is the question of how AGEs might degrade the strength and resilience of bone or cartilage. Is it via formation of cross-links, or via some other mechanism?

Working with cross-links is challenging. There are many different types of AGE, with quite different characteristics. It is not an area of molecular biochemistry that has received the attention that it deserves, and as a result there are deficiencies in the tools and understanding. Cataloging the amounts and consequences of specific types of AGE in tissues is lagging, and there are uncertainties attached to the present consensus, even the very compelling view that glucosepane is the most important age-related cross-linking AGE, and thus the best target for treatments to break down AGEs.

Given the very different effects resulting from short-lived versus persistent AGEs, or different AGEs with different biochemical interactions, it is rather important to understand the breakdown of AGEs rather than just bulk amounts of various categories of AGEs. Additionally, since AGEs tend to be produced through similar mechanisms, there is no guarantee that any particular AGE is the important damaging mechanism even if when it is unambiguously associated with disease and loss of function. Production of the AGE under consideration may be correlated with the production of many other AGE types, one of which is an important damaging agent. Thus there is a lot of work left to accomplish in this part of the field, and at least some of it will look a lot like today's open access paper.

Mass spectrometric quantitation of AGEs and enzymatic crosslinks in human cancellous bone

Material property of bone is an important determinant of bone strength. The nanoscale structures of bone are formed from collagen fibers surrounded and infiltrated with hydroxyapatite minerals. Collagen fibers provide the material properties such as tensile strength, ductility and toughness, while hydroxyapatite minerals are thought to contribute to stiffness. The functional properties of collagen are influenced by posttranslational modifications (PTMs). Among the modifications, the formation of enzymatic crosslinks between collagen fibrils are essential for physiological bone strength. On the other hand, damaging to bone strength, advanced glycation end-products (AGEs) are the results of non-enzymatic PTMs.

A series of basic and clinical trials have clarified the link between the accumulation of AGEs in bone collagen, and deterioration of bone strength. An in vitro glycation of bovine cortical bone induced pentosidine, an AGE compound, which resulted in reduced stiffness and post-yield strain. This phenomenon was also demonstrated in human cancellous bone. An in vivo study involving spontaneously diabetic rats also revealed that after the onset of diabetes, there was an increase in pentosidine accumulation in the femur with decreased bone strength despite no reduction in bone mineral density. Moreover, the link between AGEs and bone strength has been demonstrated in clinical trials. Urinary excretion of pentosidine, which is used as a surrogate marker for bone AGEs, was shown to be a predictor of vertebral fracture after adjustment for age, bone mineral density, and renal function.

In this study, we established a system that enabled the quantitation of five AGEs (CML, CEL, MG-H1, CMA and pentosidine), as well as two mature and three immature enzymatic crosslinks, in 149 human cancellous bone samples. We examined the patterns of AGEs accumulation to investigate whether pentosidine or total fluorescent AGEs (tfAGEs) more accurately reflects the actual AGEs status in bone collagen. As the clinical manifestations of AGEs accumulation include aging, diabetes and renal failure, we also analyzed the association between AGEs and the clinical parameters such as age, gender, BMI, history of diseases, glycated hemoglobin (HbA1c) as the marker of blood glycemic status over several weeks to months, tartrate-resistant acid phosphatase-5b (TRACP-5b) as the measure of bone resorption, and estimated glomerular filtration rate (eGFR).

The results showed that MG-H1 was the most abundant AGE, whereas pentosidine was 1/200-1/20-fold less abundant than the other four AGEs. The AGEs were significantly and strongly correlated with pentosidine, while showing moderate correlation with tfAGEs. In single and multiple regression analyses, gender was the strongest determinant of the AGEs, followed by age, TRACP-5b, HbA1c, and BMI. The gender difference in oxidative stress and carbonyl stress may explain this. In addition, CML and CEL, the non-crosslinking AGEs, were negatively correlated with the immature crosslinks. This result raises the possibility that non-crosslinking AGEs attribute to the deterioration of bone strength by inhibiting the formation of enzymatic crosslinks.

Existing evidence suggests that transcription of genetic blueprints into RNA becomes less coordinated with age, producing greater variance between cells. It is a question mark as to how greatly this contributes to age-related disease, and also a question mark as to exactly how it is linked to the underlying molecular damage at the root of aging. Expanding this area of research, scientists here show that within individual cells the coordination of transcription between genes also becomes dysregulated. The more age-related damage there is in tissues, the worse the dysregulation of transcription. A potential next step might be to assess this effect before and after the application of a rejuvenation therapy, such as clearance of senescent cells, in order to clearly demonstrate whether or not disruption of transcriptional coordination is a reaction to cell and tissue damage of aging.

How is it that random, disorganized damage, which accumulates differently among different humans, and moreover, among different cells of the same individual eventually leads to the same outcomes? Several theories try to address this paradox, and they have great implications for our ability to affect the aging process, making elderly life better and longer. The potential to develop treatments for aging depends on understanding the fundamental process of growing old.

A common approach holds that most cells in the human body are barely damaged during aging, while just a few "rotten apples" - a small fraction of non-functioning cells - are significantly damaged. Accordingly, a potential treatment for aging could involve removing these few highly-damaged cells. Researchers have also suggested that the proper function of biological tissues may decline during aging because many cells lose their ability to tightly regulate their genes. According to this theory, there are no single non-functioning cells - or rotten apples - on the one hand, but none of the apples is "fresh" on the other.

Using a novel approach from physics, researchers developed a computational method that quantifies the coordination level between different genes. With this approach, they measured the transcriptional activity of individual cells and compared cells from old and young subjects, discovering phenomena never before observed: old cells lost significant coordination levels compared to young cells. To test the consistency of this phenomenon, they analyzed data collected from more than twenty experiments from six different labs. In all cases they found reduced levels of coordination during aging among different organisms: human, mice, and fruit flies, and among different cell types: brain cells, hematopoietic stem cells, pancreatic cells, and more.

The researchers also observed coordination reduction in tissues with an increased level of damage, suggesting a direct link between increased damage level and coordination breakdown. The findings support the theory that during aging, accumulated random damage affects regulation mechanisms and disrupts the ability of genes to coordinate, resulting in a general decrease in tissue function. This study conclusively demonstrates the long-speculated relationship between aging, gene regulation, and somatic damage. The results open up new avenues of research with practical implications. If the same level of coordination reduction between genes is indeed a leading cause for aging phenomena, there may be a need to change course in current efforts to develop aging treatments.

Link: https://www1.biu.ac.il/indexE.php?id=33&pt=20&pid=117&level=2&cPath=33&type=1&news=3576

A fair amount of evidence points to senescent cells as causative of fibrosis, the deposition of scar-like collagen structures in tissue that disrupt organ function. This evidence includes reversal of fibrosis in animal models via selective destruction of senescent cells, a promising finding given the poor and limited options presently available for the treatment of fibrosis in human medicine. The paper here suggests that the relationship between fibrosis and cellular senescence is more complex, however, in that fibrotic changes in the extracellular matrix may act to induce greater levels of cellular senescence. Clearly there is more work to be done on this topic, but given the ability to destroy senescent cells via senolytic drugs, we might expect meaningful progress towards a better understanding in the years ahead.

Fibrotic diseases are characterised by deposition of excessive extracellular matrix (ECM) after injury resulting in organ dysfunction. While little is known about the exact mechanisms that result in excessive ECM deposition and accumulation in fibrotic disease, there is increasing evidence that cellular senescence is implicated in fibrosis. One major under-recognised element in fibrosis is the contribution of the ECM itself. It is known that the altered composition and increased cross-linking leads to an altered topography and stiffness. These changes alter cellular behaviour and might potentially drive cells to become senescent contributing to an environment favouring disease progression.

Increased ECM stiffness is a feature of fibrosis and is thought to result from the quantity of ECM deposition and the degree of its cross-linking. The mechanical properties of areas of wounded tissue significantly change in rat liver fibrosis. It was suggested that this was the result of increased cross-linking of the ECM fibres, rather than increased ECM deposition after the initial insult. These results suggest that cross-linking of ECM has a greater impact on stiffness and thus altered mechanical properties than the quantity of deposited ECM alone.

In fibrotic disease, the increased cross-linking has not only been associated with increased stiffness but also in higher resistance to proteolytic degradation as the conformational changes lead to less accessible epitopes for matrix metallopeptidases. The stiffness of the ECM directly influences the behaviour and function of cells including increased fibroblast proliferation, migration and contraction. Furthermore, a stiffer ECM leads to an increase in latent transforming growth factor-β (TGF-β) activation which reinforces fibrosis and it has been linked to cellular senescence. TGF-β contributes to the induction of senescence or the acceleration of transformation into senescence in various cell types.

Current therapeutic approaches for modulating senescence aim to specifically kill aberrant cells that have entered the senescent state. This includes several drugs (for example quercetin and dasatinib) that were originally developed for targeting tumours. However, as some of the markers that are present in malignant cells are also specifically expressed in senescent cells these agents have now been repurposed as senolytic agents. These drugs have been shown to effectively reduce the number of senescent cells, and in some cases decrease fibrosis, at least in preclinical models, potentially through modulation of the pro-inflammatory SASP released by the senescent cells.

In a first human, open label pilot study, the potential application of dasatinib and quercetin was tested in 14 patients with idiopathic pulmonary fibrosis. There was a significant improvement in the physical condition of the patients, but the pulmonary function of the patients did not change within this short trial period. Circulating SASP factors were measured, and while no significant change was reported there was a suggestion of reduced levels of selected proteins important for fibrotic remodelling, including IL-6, MMP, and TIMP2. Intriguingly, changes in pulmonary function and physical condition of the patients correlated with changes in the circulating levels of matrix remodelling proteins. While this is a very early study that needs to be validated in a much larger population in a randomised controlled trial, these observations further suggest that the role of the ECM should not be overlooked when striving to understand the regulation of senescence in fibrosis.

Link: https://doi.org/10.1042/CS20190893

The matter of buckminsterfullerene (C60) in olive oil is an instructive example of how bad work can lead a field astray for some time, but is ultimately squashed. Back in 2012, a paper was published claiming a sizable effect on life span in rats via treatment with C60 in olive oil. There were red flags at the time: it was published in a journal outside the field of aging research, used a very small number of animals, and the size of the effect on life span was just too large to be credible. Peer review would have sunk this paper if submitted to an aging-focused journal. C60 is an antioxidant, so even if it is acting in the best possible way for antioxidants to act (i.e. targeting mitochondria while leaving the rest of the cell alone) it shouldn't be doing much better than other existing mitochondrially targeted antioxidants, many of which have a fair amount of published animal data to reference.

Unfortunately, one can't ignore large effect sizes, even when they are implausible and the study that produced them looks dubious. I said at the time that this was likely to go nowhere, didn't look good on the face of it, but nonetheless people were going to spend funds on trying to replicate it and dig into the biochemistry. It took a couple of years for those efforts to start up in earnest. The Methuselah Foundation funded some of this work, alongside Longecity and a few other organizations. The Ichor Therapeutics team carried out the heavy lifting. From the get-go, the work case doubt on the original paper, discovering that C60 in olive oil is quite challenging to formulate in ways that prevent toxicity. It took some years of working at the problem to carry out a reasonable animal study.

Now, eight years later, the results of that labor are published. As suspected, this is a dead end, and that initial 2012 paper looks the worse for someone taking the time to properly close the door on this line of work. This exercise illustrates why one should apply an appropriate level of skepticism to what one reads in the literature, and why journal boards should refrain from publishing data that lies outside their area of specialty. It also shows the self-correcting nature of scientific progress at work: replication is vital, as that is how errors are checked and removed once they take place. It takes far too long and costs far too much, but remains the least worst option.

C60 in olive oil causes light-dependent toxicity and does not extend lifespan in mice

C60 is a potent antioxidant that has been reported to substantially extend the lifespan of rodents when formulated in olive oil (C60-OO) or extra virgin olive oil (C60-EVOO). Despite there being no regulated form of C60-OO, people have begun obtaining it from online sources and dosing it to themselves or their pets, presumably with the assumption of safety and efficacy.

In this study, we obtain C60-OO from a sample of online vendors, and find marked discrepancies in appearance, impurity profile, concentration, and activity relative to pristine C60-OO formulated in-house. We additionally find that pristine C60-OO causes no acute toxicity in a rodent model but does form toxic species that can cause significant morbidity and mortality in mice in under 2 weeks when exposed to light levels consistent with ambient light.

Intraperitoneal injections of C60-OO did not affect the lifespan of CB6F1 female mice. Finally, we conduct a lifespan and health span study in males and females C57BL/6 J mice comparing oral treatment with pristine C60-EVOO and EVOO alone versus untreated controls. We failed to observe significant lifespan and health span benefits of C60-EVOO or EVOO supplementation compared to untreated controls, both starting the treatment in adult or old age. Our results call into question the biological benefit of C60-OO in aging.

The transcriptome of a cell is an assessment of gene expression at a moment in time, specifically which genes have RNA transcripts under production, and the relative amounts of those transcripts. Like all such detailed cell data, the transcriptome changes with age in characteristic ways, a reaction to the presence of ever greater amounts of cell and tissue damage. Those changes can be used to produce clocks that measure biological age, very similar to the more established epigenetic clocks based on DNA methylation. The transcriptome varies by cell type, and here researchers note that combining transcriptomes from different tissues produces a more accurate result than is the case for single tissue clocks.

Studying transcriptome chronological change from tissues across the whole body can provide valuable information for understanding aging and longevity. Although there has been research on the effect of single-tissue transcriptomes on human aging or aging in mice across multiple tissues, the study of human body-wide multi-tissue transcriptomes on aging is not yet available.

In this study, we propose a quantitative model to predict human age by using gene expression data from 46 tissues generated by the Genotype-Tissue Expression (GTEx) project. Specifically, the biological age of a person is first predicted via the gene expression profile of a single tissue. Then, we combine the gene expression profiles from two tissues and compare the predictive accuracy between single and two tissues.

The best performance as measured by the root-mean-square error is 3.92 years for single tissue (pituitary), which deceased to 3.6 years when we combined two tissues (pituitary and muscle) together. Different tissues have different potential in predicting chronological age. The prediction accuracy is improved by combining multiple tissues, supporting that aging is a systemic process involving multiple tissues across the human body.

Link: https://doi.org/10.3389/fgene.2020.01025

This short commentary looks at just one cell type, T cells of the adaptive immune system, in which loss of mitochondrial function produces issues such as cellular senescence that contribute to broader degenerative aging throughout the body. Every cell contains hundreds of mitochondria, responsible for producing adenosine triphosphate, an energy store molecule used to power cellular processes. When that supply diminishes, everything suffers as a consequence: cell function, tissue function, health. With age, mitochondrial function is observed to decline throughout the body. This is likely the result of signaling and gene expression changes that hinder the quality control mechanism of mitophagy, and thus worn and damaged mitochondria are not effectively recycled. Deeper connections to the root causes of aging are not yet well understood, however.

Mitochondrial dysfunction is a key event in many pathologies and contributes to the ageing process. Mitochondria have been shown to participate in every aspect of ageing, from a decline in stem cell function and cellular senescence, through to the development of the low grade inflammatory state. Alterations that occur to mitochondria with age are numerous and can be observed in many different cells and tissues. Indeed, we have shown that human CD8+ T cells were more susceptible to senescence compared to their CD4+ counterparts as they displayed a lower mitochondrial content and postulated loss of mitochondrial function controls the senescence phenotype in T cells as well as other cell types. However the mechanism remained elusive, that is until recent work demonstrated that mitochondrial dysfunction was controlled by mitochondrial transcription factor A (TFAM).

In order to examine the links between mitochondrial loss and ageing, researchers used TFAM deficient mice, Tfamfl/flCd4Cre. TFAM is a nuclear gene that controls the stabilisation and replication of mitochondrial DNA. They found T cell mitochondrial content declined along with the loss of components of the electron transport chain causing a switch in T cell metabolism towards glycolysis. Interestingly they found young Tfamfl/flCd4Cre mice had a metabolic profile that resembled wild type 22 month mice, which was associated with Th1 skewing and increased expression of the Th1 master regulator T-bet. Additionally Tfamfl/flCd4Cre mice were also immunocompromised.

Further evidence for TFAM being associated with ageing came from the observation that 7 month Tfamfl/flCd4Cre mice had an elevated inflammatory burden or inflammageing more usually seen in older animals. This increased inflammation is a predictor of multimorbidity during ageing and Tfamfl/flCd4Cre mice were found to have premature loss of muscular, cardiovascular, and cognitive fitness together with a shorten life span. TFAM deficient animals were found to be less active and slower with less hypodermal fat than controls despite a higher energy expenditure.

The authors validated that this multimorbidity phenotype was due to a mitochondrial defect specifically in T cells by creating a T cell-specific Tfam deficient mouse model, Tfamfl/flLckCre. These animals also showed a prematurely aged phenotype by elevated expression of the senescence-associated markers p21 and p53. Incubation of hepatocytes or pre-adipocytes with serum from Tfamfl/flCd4Cre animals or with TNFα also increased p21 expression, supporting the idea that inflammation induces senescence and premature ageing. They also gave Tfamfl/flCd4Cre animals nicotinamide riboside (NR), the NAD+ precursor that declines with age and is a metabolic cofactor with a critical role in mitochondrial function. The use of NR was found to be protective against premature senescence and most but not all features of multimorbidity.

The paper concludes that T cells are capable of regulating both health and lifespan as well as highlighting the importance of tight immunometabolic control during ageing and the onset of age-related diseases. Finally, this work cements the idea that mitochondria play a causal role in senescence and that increasing mitochondrial biogenesis when coupled with mitochondrial degradation confers a survival advantage at both the cellular and organismal level.

Link: https://doi.org/10.20900/immunometab20200035

You might recall that OneSkin recently launched a cosmetic product claimed to reduce levels of senescent cells in aged skin, as measured by the usual markers for cellular senescence, such as p16 expression and senescence-associated β-galactosidase. Removal of senescent cells is more or less literal rejuvenation, given that the accumulation of such cells drives chronic inflammation, tissue dysfunction, and degenerative aging. Clearance of a large fraction of senescent cells via senolytic drugs has been shown to extend life and turn back measures of aging in a number of animal studies.

The OneSkin product contains a bunch of the usual things one puts into skin care products, all of which can be safely ignored, but the core of it is peptide 14, also called OS-01 and decapeptide-52. This may or may not be a senolytic compound, capable of selectively destroying senescent cells to some degree. The evidence presented in today's preprint paper suggests that the observed effect on markers of cellular senescence is more likely achieved by preventing at least some cells from entering the senescent state.

In this, the use of peptide 14 might be similar in outcome to the topical application of rapamycin. In that case, researchers are fairly confident that no direct destruction of senescent cells is taking place, only a reduction in senescent cell creation and activity. This can be enough in aged skin to allow existing processes of senescent cell clearance to catch up over a timescale of a few months, and meaningful reduce the number of these errant cells and their impact on tissue function. Interestingly, the OneSkin folk used rapamycin as a positive control, and found it worsened aspects of their skin models even as it lowered markers of cellular senescence - so perhaps not something to dive into until more data has accumulated.

Looking at the meat of the data in this preprint, peptide 14 performs as well or better than topical rapamycin in reducing markers of cellular senescence, at least in skin models and in skin biopsies taken from older volunteers. Formal trials and resulting human data are pending - though the product is available for anyone who wants to give it a try. Given the existing data, it will be interesting to see how the product performs in older people in comparison to topical rapamycin use.

Senotherapeutic peptide reduces skin biological age and improves skin health markers

Skin aging has been primarily related to aesthetics and beauty. Therefore, interventions have focused on reestablishing skin appearance, but not necessarily skin health, function, and resilience. Recently, cellular senescence was shown to play a role in age-related skin function deterioration and influence organismal health and, potentially, longevity.

In the present study, a two-step screening was performed to identify peptides capable of reducing cellular senescence in human dermal fibroblasts (HDF) from Hutchinson-Gilford Progeria (HGPS) patients. From the top four peptides of the first round of screening, we built a 764-peptide library using amino acid scanning, of which the second screen led to the identification of peptide 14. Peptide 14 effectively decreased HDF senescence induced by HGPS, chronological aging, ultraviolet-B radiation, and etoposide treatment, without inducing significant cell death, and likely by modulating longevity and senescence pathways.

We further validated the effectiveness of peptide 14 using human skin equivalents and skin biopsies, where peptide 14 promoted skin health and reduced senescent cell markers, as well as the biological age of samples, according to the Skin-Specific DNA methylation clock, MolClock. Topical application of peptide 14 outperformed Retinol treatment, the current gold-standard in "anti-aging" skin care. Finally, we determined that peptide 14 is safe for long-term applications and also significantly extends both the lifespan and healthspan of C. elegans worms tested in two independent testings. This highlights the potential for geroprotective applications of the senotherapeutic compounds identified using our screening platform beyond the skin.

The SynergyAge database is intended to collect information on interactions between longevity-related mutations. Many such genetic alterations have been studied in laboratory species - yeast, flies, worms, mice, and so forth - but interactions between mutations are only sparsely investigated in comparison. This is true for all interventions in aging, as a rule. The scientific and development communities operate under incentives that tend to steer them away from combining effects in search of a larger outcome when it comes to slowed or reversed aging. This is already a problem now, in the early stages of the era of treating aging as a medical condition, and will become more pressing in the years ahead as effective means of addressing the molecular damage of aging continue to emerge.

Genetic mutants have been observed with lifespan, up to ten times longer compared to wild type in C. elegans, and up to 150% and 46% in D. melanogaster and M. musculus, respectively. In model organisms, at least 2,205 genes have been identified to produce a long-lived or short-lived phenotype when mutated, knocked down, or overexpressed. A comprehensive list of these longevity-associated genes (LAGs), including more detailed information about lifespan experiments, can be found in the GenAge database.

This type and amount of data have made it possible to perform higher-level analyses, and the collection of LAGs in public repositories has significantly pushed biogerontology towards more integrative approaches to study longevity. One important aspect observed is that many LAGs seem to act in a cooperative manner and are not independent regulators of lifespan. In fact, in most cases when combining two or more genetic interventions, the effect is rarely additive, as genes are generally epistatic and interact in nonlinear ways. While in most cases combined interventions seem to have lower than expected results in how much they extend lifespan, there are also a minority of cases where genes act synergistically. Even so, the much more common case is that of studies where partially dependent gene interactions are revealed, making it even more important to understand and predict genetic dependencies.

Unfortunately, data on epistasis is much harder to obtain through wide-screen experimental studies, which has been for example the case for the discovery of most LAG interventions in worms. The main impediment comes from the combinatorial explosion of multiple gene groups for which lifespan assays would need to be measured in a "blind" search, through wet-lab experiments. A more efficient approach is to use existing epistasis data to explore predicted synergies in guided lifespan experiments. Fortunately, an accumulating number of papers has been published in the last two decades with reported lifespans for double, triple, and even quadruple mutants. As such, it has been now possible for us: (i) to collect the data from existing studies containing lifespan records for strains that have multiple genes modulated, and (ii) to create an intuitive, network-based tool, which allows users to explore in a fast, visual and interactive way the lifespan relationships between these strains.

As a step towards applying predictive methods, but also to provide information for a guided design of epistasis lifespan experiments, we developed SynergyAge - a database containing genetic and lifespan data for animal models obtained through multiple longevity-modulating interventions. The studies included in SynergyAge focus on the lifespan of animal strains which are modified by at least two genetic interventions, with single gene mutants included as reference. SynergyAge, which is publicly available, provides an easy to use web-platform for browsing, searching and filtering through the data, as well as a network-based interactive module for visualization and analysis.

Link: https://doi.org/10.1038/s41597-020-00710-z

The APOE gene has a number of common variants that are known to correlate with differences in human life expectancy, as well as with Alzheimer's disease risk. Researchers here show that there are life expectancy effects distinct from any impact of Alzheimer's disease on life span. If including the whole population, those with and without dementia, there is about a five year difference in the time taken to reach 50% mortality in a cohort between the best (APOE2) and worst (APOE4) variants.

The non-dementia-impacting mechanisms by which this difference in life expectancy manifests are presently unknown. While aging has root causes that are fairly well catalogued at this point, the way in which aging unfolds from those root causes is very complex, and still poorly mapped. This is exactly why more effort should go towards repairing the root causes rather than tinkering with the operation of metabolism later stages of aging. That some gene variants affect the progression of aging is interesting, but largely irrelevant to any meaningful effort to produce rejuvenation, as that effort should focus on first causes rather than downstream processes.

Although the ε2 allele of apolipoprotein E (APOE2) benefits longevity, its mechanism is not understood. The protective effects of the APOE2 on Alzheimer's disease (AD) risk, particularly through their effects on amyloid or tau accumulation, may confound APOE2 effects on longevity. Herein, we showed that the association between APOE2 and longer lifespan persisted irrespective of AD status, including its neuropathology, by analyzing clinical datasets as well as animal models.

Notably, APOE2 was associated with preserved activity during aging, which also associated with lifespan. In animal models, distinct apoE isoform levels, where APOE2 has the highest, were correlated with activity levels, while some forms of cholesterol and triglycerides were associated with apoE and activity levels. These results indicate that APOE2 can contribute to longevity independent of AD. Preserved activity would be an early-observable feature of APOE2-mediated longevity, where higher levels of apoE2 and its-associated lipid metabolism might be involved.

Link: https://doi.org/10.7554/eLife.62199

Cells enter a senescent state constantly throughout life, largely because they have reached the Hayflick limit on replication, but also due to molecular damage, cancerous mutations, injury to tissue, radiation, or other causes. A senescent cell stops replicating, swells in size, and begins to secrete a mix of inflammatory signals, growth factors, and other molecules. Near all senescent cells are destroyed rapidly, either by programmed cell death or by the immune system, but this stops being the case in later life. Lingering senescent cells accumulate, and signaling that is helpful in the short term, to suppress cancer or aid in healing from injury, becomes disruptive and harmful when sustained over the long term. Senescent cells contribute meaningfully to age-related chronic inflammation, tissue dysfunction, and disease.

The biochemistry of senescence is not as well understood and catalogued as one might expect for a phenomenon that has been studied in one context for another for decades. Only in the past decade has the connection to aging been accepted by the broader research community, but now a great many research groups are mining the biology of senescence in search of ways to suppress the bad behavior of these cells, or selectively destroy them. That last option seems very feasible as a basis for therapy, given that there are never a great many of these cells in the body, even in late old age, and selective destruction via senolytic treatments extends life and reverses numerous manifestations of age-related disease in mice.

Today's research materials are an interesting example of ongoing work that may lead to a taxonomy of the state of senescence. It is likely that different tissues and cell types exhibit meaningful differences in senescent cell biochemistry. Further, it appears that senescence isn't a blanket single phenomenon, but rather distinctions can be made between different stages or phenotypes of senescence. It remains to be determined with any great rigor as to how cells determine which type of senescence they adopt, or how they shift between states within senescence, or how this knowledge might be applied to better produce rejuvenation by targeting senescent cells.

Aged cell variations may control health and onset of age-related diseases

Researchers have proposed that cellular senescence variations during the aging process could lead to control of health and onset of age-related diseases. Based on the characteristics of the secretion of inflammatory cytokines released by aged cells, they hypothesize that there are at least four distinct states of cellular senescence, and that these four states arise from coordinated metabolic and epigenomic changes. The states: 1. initiation (proliferation arrest), 2. early (anti-inflammation), 3. full (increased inflammation and metabolism), and 4. late (decreased inflammation and metabolism). Characterizing and categorizing qualitatively different states of cellular senescence could provide a new understanding of the aging and senescence process.

Many of the cells that make up the body eventually decline in function and stop growing after repeated divisions in a process called "cellular senescence," an important factor in health and longevity. Premature senescence occurs when genomic DNA is damaged by stressors such as radiation, ultraviolet light, or drugs, but its mechanisms are not yet fully understood. It can be good, like when cells become cancerous, cellular senescence works to prevent the development of malignancy, but it also increases the likelihood of many age-related diseases. It is therefore important for medical science to try to understand and control it.

Although senescent cells lose their ability to proliferate, recent research has shown that they secrete various proteins that act on surrounding cells and promote chronic inflammation and cancer cell growth. This is called the senescence-associated secretory phenotype (SASP). Cellular senescence is thought to be the cause of aging in the entire body. Senescent cells have been shown to accumulate in the bodies of aged mice, and removal of these cells may suppress whole-body aging. In other words, if cellular senescence is controlled, it may become possible to regulate the aging process of the whole body.

Cellular Senescence Variation by Metabolic and Epigenomic Remodeling

Cellular senescence involves at least four distinguishable states in chronological order (initiation, and early, full, and late senescence), which are especially classified by metabolism and SASP features. Under the action of senescenceinducing stresses, the p53-p21 CIP1 and p16 INK4a -retinoblastoma (RB) pathways cause cell cycle arrest at senescence initiation. In early senescence, transforming growth factor (TGF)β is produced possibly for anti-inflammatory defense at least in part via the Notch1-mediated pathway (TGFβ SASP) with increasing morphological changes such as an enlarged cell size.

Then, in full senescence, metabolic activation yields many metabolites, cellular energy, and reactive oxygen species that accelerate senescence progression with secretion of proinflammatory cytokines such as IL-6 and IL-8 (proinflammatory SASP). The levels of proinflammatory SASP tend to be high in oncogene-induced senescence, and low in replicative senescence. Microscopically, fully senescent cells often exhibit cytoplasmic SA β-Gal positivity and nuclear SAHF.

Finally, interferon secretion and metabolic decline occur in late senescence (interferon SASP). In full to late senescence, accumulation of cytoplasmic DNAs activates the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway for cytosolic DNA sensing and the interferon response. Thus, there are at least four different states of cellular senescence, suggesting that senescent cells diversely have metabolic and secretory phenotypes.

There is a blurry gray area between intermittent fasting and time restricted feeding. The study here is somewhere in that zone, as the participants did eat daily, with less fasting time between meals than would be the case for, say, alternate day fasting. Time spent hungry does appear to be influential to the outcome, but perhaps less so than overall calories consumed. Inevitably, people eat fewer calories if given less time in which to consume calories. Unsurprisingly, eating less improves metrics in people with metabolic syndrome, a condition achieved by being overweight as a result of eating too much. The point of interest here is the specific metrics measured and the results: by now we all know that calorie restriction and fasting are beneficial, but there is plenty of work yet to do when it comes to quantifying those benefits.

Metabolic syndrome is characterized by central obesity, insulin resistance, elevated blood pressure, and dyslipidemia. Metabolic syndrome is a significant risk factor for several common cancers (e.g., liver, colorectal, breast, pancreas). Pharmacologic treatments used for the components of the metabolic syndrome appear to be insufficient to control cancer development in subjects with metabolic syndrome. Murine models showed that cancer has the slowest progression when there is no food consumption during the daily activity phase. Intermittent fasting from dawn to sunset is a form of fasting practiced during human activity hours. To test the anticancer effect of intermittent fasting from dawn to sunset in metabolic syndrome, we conducted a pilot study in 14 subjects with metabolic syndrome who fasted (no eating or drinking) from dawn to sunset for more than 14 hours daily for four consecutive weeks.

We collected serum samples before 4-week intermittent fasting, at the end of 4th week during 4-week intermittent fasting and 1 week after 4-week intermittent fasting. We performed serum proteomic analysis using nano ultra-high performance liquid chromatography-tandem mass spectrometry. We found a significant fold increase in the levels of several tumor suppressor and DNA repair gene protein products (GP)s at the end of 4th week during 4-week intermittent fasting (CALU, INTS6, KIT, CROCC, PIGR), and 1 week after 4-week intermittent fasting (CALU, CALR, IGFBP4, SEMA4B) compared with the levels before 4-week intermittent fasting. We also found a significant reduction in the levels of tumor promoter GPs at the end of 4th week during 4-week intermittent fasting (POLK, CD109, CAMP, NIFK, SRGN), and 1 week after 4-week intermittent fasting (CAMP, PLAC1) compared with the levels before 4-week intermittent fasting.

Fasting from dawn to sunset for four weeks also induced an anti-diabetes proteome response by upregulating the key regulatory proteins of insulin signaling at the end of 4th week during 4-week intermittent fasting (VPS8, POLRMT, IGFBP-5) and 1 week after 4-week intermittent fasting (PRKCSH), and an anti-aging proteome response by upregulating H2B histone proteins 1 week after 4-week intermittent fasting. Subjects had a significant reduction in body mass index, waist circumference, and improvement in blood pressure that co-occurred with the anticancer, anti-diabetes, and anti-aging serum proteome response. These findings suggest that intermittent fasting from dawn to sunset actively modulates the respective genes and can be an adjunct treatment in metabolic syndrome. Further studies are needed to test the intermittent fasting from dawn to sunset in the prevention and treatment of metabolic syndrome-induced cancers.

Link: https://doi.org/10.1038/s41598-020-73767-w

NAD+ metabolism in the context of aging and age-related disease is an area of some interest of late. NAD+ is involved in mitochondrial function, essential to cell and tissue function. The mechanisms of synthesizing and recycling NAD+ decline with age, and this might be an important contributing factor in the decline of mitochondrial function throughout the body. Certainly, the evidence in cells and animals suggests that mitochondrial function can be improved via restoration of youthful levels of NAD+.

Given that the available ways of manipulating NAD+ metabolism largely involve supplementation with vitamin B3 derivatives, such as niacin, nicotinamide riboside, and nicotinamide mononucleotide, much of this research in human patients is effectively a slightly more sophisticated extension of decades of clinical trials of high dose vitamin B3. As a recent review notes, the results to date have been hit and miss, as yet not that much better than can be obtained through exercise programs, but some degree of benefit to older individuals appears plausible.

Altered NAD+ homeostasis has been linked to multiple diseases affecting different organs, including the brain and nervous system, liver, heart and kidney. NAD+ depletion is a hallmark of ageing and numerous age-related disorders. Therefore, boosting NAD+ offers a promising option for enhancing resilient to aging or diseases, thereby extending a healthy lifespan. The NAD+ level can be elevated by dietary supplementation of NAD+ precursors, such as tryptophan, niacin (NA), nicotinamide mononucleotide (NMN), and nicotinamide riboside (NR), inhibition of NAD+-consuming enzymes, including PARP1 and CD38, management of the NAD+ biosynthesis via controlling NAD+-biosynthesis enzymes, or improving NAD+ bioavailability through exercise and caloric restriction.

NAD+ precursors can be used as a nutritional supplement to improve a broad spectrum of physiological functions and pathological processes. The therapeutic and preventive efficacy of NAD+ boosters, especially the soluble and orally bioavailable endogenous molecules NR, nicotinamide (NAM), and NA, have been assessed in a series of clinical trials in humans. Findings suggest that elevating NAD+ levels by administration of NAD+ precursors, including NMN, NR, NAM, and NA, is a rational therapeutic strategy to improve a healthy lifespan. Given that NAD+-depleting drugs exhibit anti-tumor potential due to their impact on DNA repair and inflammation, long-term boosting NAD+ might increase the risk of driving tumor growth. Moreover, the detrimental side effects of NAD+ and its intermediates may be caused by the NAD+-dependent sirtuins that have both oncogenic and tumor suppressive activity in different contexts. Consistent with this hypothesis, NMN treatment accelerates pancreatic cancer progression via creating an inflammatory environment. Thus, future clinical studies are necessary to assess the long-term safety of NAD+ precursors in human therapeutics.

The levels and compartmentalization of NAD+ dictate energy state that impinges on normal physiological and biological responses, as indicated by the regulatory role of NAD+ in proper redox homeostasis, genomic stability, gene expression, circadian clock, inflammation, metabolism, cellular bioenergetics, mitochondrial homeostasis, and adaptive stress responses. A healthy lifestyle and exercise are non-pharmacologic strategies to improve the body's resilience and extend healthy lifespan through enhancing NAD+ levels. NAD+ boosters can be applied for a broad spectrum of NAD+ deficiency related pathologies, such as infection, cancer, metabolic diseases, acute injury, aging, and aging-related neurodegenerative disorders. Conceivably, this could be achieved by boosting NAD+ via enhancing the NAD+ generation and diminishing NAD+ consumption.

Despite exciting and emerging strides in NAD+ biology, there are a variety of outstanding questions that warrant future systematic exploitation to accelerate the translation of remarkable bench work to effective clinical application in humans. The first interesting question is that the precise mechanisms executing the beneficial effects of NAD+ and its metabolites on pathologies and lifespan remain elusive. Further investigation understanding the landscape of NAD+ in response to diseases and identifying the specific effector molecules for each NAD+ precursors at different time points provide critical insights into development of effective interventions for various physiologies. Secondly, the systemic NAD+ metabolome is largely unexplored. Are there any tissue specificities for NAD+ boosting, such tissue preferences of distinct NAD+ precursors? What is the crosstalk with the NAD+ systems of each organ? What is the distinct NAD+ metabolome in each tissue? In spite of growing interest in the use of NAD+ precursors as a strategy for healthy aging, the in vivo pharmacokinetics remain poorly understood.

Link: https://doi.org/10.1038/s41392-020-00311-7

It remains challenging to produce large or thick sections of engineered tissue because there is no widely adopted, feasible approach to creating sufficient dense and structured blood vessel networks. A capillary network is needed to supply the inner sections of larger blocks of tissue, and without this networking cells die due to lack of nutrients and oxygen. While some very promising lines of work exist, such as that under development at Volumetric, they are not yet broadly employed in the research community. This state of affairs limits the applications of tissue engineering to cases in which thin sheets of tissue can be useful, such as the production of a patch for a damaged heart. Even in this type of application, however, and as demonstrated in today's research materials, being able to engineer some form of vascular network improves the outcome considerably.

Researchers have for a few years demonstrated the ability to apply patches of engineered tissue to an injured heart. Various attempts have varied from very simple biodegradable scaffolds that are only intended to increase the survival time of transplanted stem cells and heart muscle cells, to produce a better effect than direct injection of cells into cardiac tissue, to quite sophisticated pseudo-tissue structures, containing chemical cues and varied cell populations, that integrate into the vasculature of the heart. Applying such patches appears a fairly promising approach to increase survival and heart function following heart attack or other damage, but it has yet to make it to the clinic.

A patch that could help heal broken hearts

During a heart attack, or myocardial infarction (MI), a blocked artery and the resulting oxygen deprivation cause massive cardiac cell death, blood vessel impairment, and inflammation. To effectively treat MI, lost heart muscle tissue must regenerate and new blood vessels must form to restore oxygen and nutrients to cells. Scientists have tried to develop patches containing various therapeutic cells to treat MI, but so far most have been too cumbersome to make, or they don't restore both cardiac muscle and blood supply to the injured site. Researchers previously developed a relatively easy-to-make pre-vascularized cardiac patch, which contained engineered microvessels in a fibrin gel spiked with cardiac stromal cells. When implanted into rats after an MI, the cells in the patch secreted growth factors that made cardiac muscle and blood vessels regrow. Now, the researchers wanted to test the patch further in rats, as well as in pigs, which have cardiovascular systems more similar to humans than those of rodents.

The researchers implanted the cardiac patch in rats that recently had a heart attack. Four weeks later, rats that received the patch had less scar tissue, increased cardiac muscle, and improved cardiac pump function compared with untreated rats. The team observed similar effects in pigs that had undergone MI and were treated with the patches. The patch increased recruitment of the pigs' progenitor cells to the damaged area and enhanced the growth of new blood vessels, as well as decreased cardiac cell death and suppressed inflammation. Although prior studies have used blood vessel-forming cells or natural blood vessels to vascularize cardiac patches, this study is the first to demonstrate the success of pre-vascularized cardiac stromal cell patches using microengineered synthetic blood vessels for treating MI in a large animal model.

Cardiac Stromal Cell Patch Integrated with Engineered Microvessels Improves Recovery from Myocardial Infarction in Rats and Pigs

The vascularized cardiac patch strategy is promising for ischemic heart repair after myocardial infarction (MI), but current fabrication processes are quite complicated. Vascularized cardiac patches that can promote concurrent restoration of both the myocardium and vasculature at the injured site in a large animal model remain elusive. The safety and therapeutic benefits of a cardiac stromal cell patch integrated with engineered biomimetic microvessels (BMVs) were determined for treating MI. By leveraging a microfluidic method employing hydrodynamic focusing, we constructed the endothelialized microvessels and then encapsulated them together with therapeutic cardiosphere-derived stromal cells (CSCs) in a fibrin gel to generate a prevascularized cardiac stromal cell patch (BMV-CSC patch).

We showed that BMV-CSC patch transplantation significantly promoted cardiac function, reduced scar size, increased viable myocardial tissue, promoted neovascularization, and suppressed inflammation in rat and porcine MI models, demonstrating enhanced therapeutic efficacy compared to conventional cardiac stromal cell patches. BMV-CSC patches did not increase renal and hepatic toxicity or exhibit immunogenicity. We noted a significant increase in endogenous progenitor cell recruitment to the peri-infarct region of the porcine hearts treated with BMV-CSC patch as compared to those that received control treatments. These findings establish the BMV-CSC patch as a novel engineered-tissue therapeutic for ischemic tissue repair.

The brain is very complex, and so the ways in which comparatively simple mechanisms of aging lead to alterations in cognitive function are also very complex. The research here picks up the trail of cause and effect relating to changes in approach-avoidance conflict, a part of decision making, a fair way down the line from first causes, as is the case for much of the work taking place on the aging of the brain. It is nonetheless always interesting to see specific age-related changes in complex traits connected to specific cells and their activity, even when the further connections to underlying mechanisms of aging remain obscure.

The striatum is part of the basal ganglia - a collection of brain centers linked to habit formation, control of voluntary movement, emotion, and addiction. For several decades, researchers have studied clusters of cells called striosomes, which are distributed throughout the striatum. Their function had remained mysterious, in part because they are so small and deep within the brain that it is difficult to image them with functional magnetic resonance imaging.

In recent years, researchers have discovered that striosomes play an important role in a type of decision-making known as approach-avoidance conflict. These decisions involve choosing whether to take the good with the bad - or to avoid both - when given options that have both positive and negative elements. An example of this kind of cost-benefit decision is having to choose whether to take a job that pays more but forces a move away from family and friends. Such decisions often provoke great anxiety.

In a related study, researchers found that striosomes connect to cells of the substantia nigra, one of the brain's major dopamine-producing centers. These studies led the researchers to hypothesize that striosomes may be acting as a gatekeeper that absorbs sensory and emotional information coming from the cortex and integrates it to produce a decision on how to act. These actions can then be invigorated by the dopamine-producing cells.

Researchers found that in older mice (between 13 and 21 months, roughly equivalent to people in their 60s and older), the mice's engagement in learning this type of cost-benefit analysis went down. At the same time, their striosomal activity declined compared to that of younger mice. The researchers found a similar loss of motivation in a mouse model of Huntington's disease, a neurodegenerative disorder that affects the striatum and its striosomes. When the researchers used genetically targeted drugs to boost activity in the striosomes, they found that the mice became more engaged in performance of the task. Conversely, suppressing striosomal activity led to disengagement. The researchers are now working on possible drug treatments that could stimulate this circuit.

Link: https://news.mit.edu/2020/why-learn-motivate-age-decline-1027

Researchers here report on their investigation of mechanisms underlying the ability of physical activity to improve muscle regeneration. As it turns out, exercise alters metabolism in muscle stem cells in a way that increases their activity in support of tissue function. Identifying more specific mechanisms involved in the way in which exercise improves function will no doubt give rise to a broader range of efforts to produce exercise mimetic drugs that replicate some of these effects. That said, this sort of work has been ongoing for a while and is, overall, a slow business, just like the development of calorie restriction mimetic compounds. So far neither field has produced options that are evidently better as an option than simply exercising.

Skeletal muscle stem cells (satellite cells) are well known to participate in regeneration and maintenance of the tissue over time. Studies have shown increases in the number of satellite cells after exercise, but their functional role in endurance training remains unexplored. In this study, young adult mice were submitted to endurance exercise training and the function, differentiation, and metabolic characteristics of satellite cells were investigated in vivo and in vitro.

We found that injured muscles from endurance-exercised mice display improved regenerative capacity, demonstrated through higher densities of newly formed myofibres compared with controls (evidenced by an increase in embryonic myosin heavy chain expression), as well as lower inflammation (evidenced by quantifying CD68-marked macrophages), and reduced fibrosis. Enhanced myogenic function was accompanied by an increased fraction of satellite cells expressing self-renewal markers, while control satellite cells had morphologies suggestive of early differentiation.

The beneficial effects of endurance exercise were associated with satellite cell metabolic reprogramming, including reduced mitochondrial respiration (O2 consumption) under resting conditions (absence of muscle injury) and increased stemness. During proliferation or activated states (3 days after injury), O2 consumption was equal in control and exercised cells, while exercise enhanced myogenic colony formation. Surprisingly, inhibition of mitochondrial O2 consumption was sufficient to enhance muscle stem cell self-renewal characteristics in vitro. Moreover, transplanted muscle satellite cells from exercised mice or cells with reduced mitochondrial respiration promoted a significant reduction in inflammation compared with controls.

Our results indicate that endurance exercise promotes self-renewal and inhibits differentiation in satellite cells, an effect promoted by metabolic reprogramming and respiratory inhibition, which is associated with a more favourable muscular response to injury.

Link: https://doi.org/10.1002/jcsm.12601

Focused ultrasound is one of the many approaches used to directly kill cancer cells once they have grown to the point at which a tumor can be identified. It involves generating sufficient heat to kill cells, a fairly direct transfer of energy. Pruning back cancerous tissue is helpful, as tumors manipulate the signaling environment to subvert the immune system's ability to destroy cancerous cells, and constantly generate new mutations that ultimately lead to metastasis and the spread of a cancer throughout the body.

Removing tumor tissue in this way is not a cure, however. Curing cancer requires not just the removal of bulk tumors, but also other means that can be deployed to destroy all lingering or metastasized cancerous cells, any small collection of which can start up a tumor once again. The challenge inherent in any mechanical or radiation based removal of tumors is that it is rarely complete enough to prevent recurrence, while the challenge inherent in any small molecule, gene therapy, immunotherapy, or other similar systemically delivered approach is that tumor masses are a different and tougher target than distributed cancer cells.

Ultrasound ablation of tumor tissue has the advantage of avoiding surgery, but the disadvantage of causing just as much collateral damage to tissues as surgery. Today's research materials discuss ways to minimize that damage, by minimizing cavitation, the formation of heated microbubbles that can spread to destroy tissue surrounding the target. Modeling of outcomes in the use of ultrasound ablation is already something of an art form, with a large variation between predicted and actual results, so it is an open question as to how well this additional layer of modeling will work in practice.

Destroying cancer cells with non-surgical ultrasound treatment

Focusing ultrasound energy on a target site in the body to generate heat can burn and destroy the tissue in the site without a surgical procedure. This method is clinically applied to treat uterine fibroids, prostatic hyperplasia, prostate cancer, metastatic bone tumor and other types of tumor to destroy tumor cells using heat. However, there is a potential problem that the surrounding tissue may be burned in the process due to heat diffusion.

In 2019 a research team confirmed the possibility of precisely fractionating target tumor cells, as though it is cut out using a knife, without causing heat damage to any other part of the body by using high-intensity focused ultrasound (HIFU), an ultrasound with an acoustic pressure that is much more powerful than existing ultrasound. In the process of physically destroying the tissue without the use of heat, a boiling vapor bubble is generated at the target site of the HIFU, and it is by the kinetic energy of this primary vapor bubble that the target tumor tissue gets destroyed. However, during the process, cavitation bubble clouds can be subsequently generated between the boiling bubble and the HIFU transducer, leading to unwanted cell destruction. This made it necessary to identify the cause of their formation and to accurately predict the locations of their occurrence.

Results showed that the secondary generation of bubbles was caused by a constructive interference of the backscattered shockwave by the boiling bubble with the incoming incident shockwaves and it is within the range of this interference that the secondary bubbles formed. Based on the images obtained using a high-speed camera, it was found that the area where the interference occurred and the area where the secondary bubbles were generated were closely matched. These findings not only explain the mechanism behind the secondary bubbles formation but also help predict where they will occur, thereby presenting the possibility of destroying target tissue with greater safety and precision.

The interaction of shockwaves with a vapour bubble in boiling histotripsy: The shock scattering effect

Boiling histotripsy is a High Intensity Focused Ultrasound (HIFU) technique which uses a number of short pulses with high acoustic pressures at the HIFU focus to induce mechanical tissue fractionation. In boiling histotripsy, two different types of acoustic cavitation contribute towards mechanical tissue destruction: a boiling vapour bubble and cavitation clouds. An understanding of the mechanisms underpinning these phenomena and their dynamics is therefore paramount to predicting and controlling the overall size of a lesion produced for a given boiling histotripsy exposure condition. A number of studies have shown the effects of shockwave heating in generating a boiling bubble at the HIFU focus and have studied its dynamics under boiling histotripsy insonation. However, not much is known about the subsequent production of cavitation clouds that form between the HIFU transducer and the boiling bubble.

The main objective of the present study is to examine what causes this bubble cluster formation after the generation of a boiling vapour bubble. Our results suggest that the formation of a cavitation cloud in boiling histotripsy is a threshold effect which primarily depends (a) the size and location of a boiling bubble, and (b) the sum of the incident field and that scattered by a bubble.

Researchers have identified a subset of the population of the immune cells called neutrophils that can promote nervous system regeneration. Nerves are one of the least regenerative tissue types, and thus numerous research groups are in search of ways to promote nerve regeneration following injury, or to promote better maintenance of nervous system tissue in later life. The example here is an interesting one; the immune system is deeply involved in regeneration, and it makes sense for there to be ways to manipulate that relationship, even quite crudely, such as by finding specific classes of immune cell and increasing their numbers in injured tissue.

Using a mouse model, researchers discovered a new type of immune cell that not only rescues damaged nerve cells from death, but partially reverses nerve fiber damage. The research team also identified a human immune cell line, with similar characteristics, that promotes nervous system repair. "This immune cell subset secretes growth factors that enhance the survival of nerve cells following traumatic injury to the central nervous system. It stimulates severed nerve fibers to regrow in the central nervous system, which is really unprecedented."

The cell discovered by these researchers is a granulocyte, a type of white blood cell that has small granules. The most common granulocytes, neutrophils, normally help the body fight off infection. The unique cell type resembles an immature neutrophil but is distinctive in possessing neuroprotective and neuroregenerative properties. It drives central nervous system axon (nerve) regrowth in vivo, in part through the secretion of a cocktail of growth factors. "We found that this pro-regenerative neutrophil promotes repair in the optic nerve and spinal cord, demonstrating its relevance across central nervous system compartments and neuronal populations. A human cell line with characteristics of immature neutrophils also exhibited neuroregenerative capacity, suggesting that our observations might be translatable to the clinic."

Researchers demonstrated the therapeutic potency of the immature neutrophil subset by injecting them into mice with crush injury to the optic nerve or lacerated nerve fibers in the spinal cord. Mice injected with the new neutrophil subset, but not more typical mature neutrophils, grew new nerve fibers.

Link: https://www.eurekalert.org/pub_releases/2020-10/m-don101920.php

Researchers here note that the FOXO signaling pathway appears to help maintain function in a subset of muscle stem cells all the way into later life. Muscle stem cell activity declines with age, even while the evidence suggests that the populations are largely intact and able to act if placed into a more youthful environment. This decline may be an evolved reaction to the molecular damage of aging that serves to reduce the cancer risk inherent in cell activity in a damaging environment, or it may be the consequence of damage and dysfunction in the stem cell niche in which muscle stem cells reside, or both. This loss of stem cell activity is an important contributing cause of sarcopenia, the age-related loss of muscle mass and strength that affects all individuals to an ever increasing degree over time. Thus the research community is interested in the discovery of ways to put aging muscle stem cells back to work.

Skeletal muscle regeneration depends on a muscle stem cell population (satellite cells) in a dormant or quiescent state, a situation that can be triggered by damage or stress to form new muscle fibres and expand in new stem cells. The regenerative functions of these stem cells are known to decline with ageing. Researchers have found in experiments with mice that all muscle stem cells, despite being quiescent, are not equal, and have identified a subgroup that maintains its regenerative capacity over time, declining only at geriatric age.

The researchers have shown that this subgroup of quiescent stem cells has a greater regenerative capacity through the activation of the FoxO signalling pathway (previously associated with longevity), which maintains the expression of a youthful gene programme throughout life; however, at geriatric age, FoxO activation in this subgroup of cells is lost, causing their loss of functionality.

According to the results, compounds that activate FoxO may have a rejuvenating effect on aged muscle stem cells, opening the way to improve the health of elderly people who are debilitated by the loss of muscle mass. It may also be useful for persons who have lost muscle mass as a result of neuromuscular diseases or effects associated with cancer or infectious or inflammatory diseases.

Link: https://www.eurekalert.org/pub_releases/2020-10/upf--ias102720.php

We live in the early, formative years of the era of rejuvenation, in which medicine will target the mechanisms of aging, increasingly effectively as the years pass, in order to make the old physiologically young once again. The first, crude rejuvenation therapies worthy of the name are under development or already available to the adventurous. These are senolytic treatments that selectively destroy the accumulated senescent cells that contribute to aging. Senescent cells produce chronic inflammation, tissue dysfunction, and age-related disease. By removing even just a third to a half of senescent cells in just some tissues, mice have been rejuvenated, their healthy life spans extended, and numerous age-related conditions reversed. Biotech companies are developing drugs and running trials. Human patients will be next.

It isn't an accident that this is happening now. The non-profit SENS Research Foundation and Methuselah Foundation are two small but important organizations that have, since shortly after the turn of the century, worked tirelessly to (a) change the culture of the scientific community to focus on the possibility of treating aging as a medical condition, (b) unblock stalled areas of important research into repairing the molecular damage that causes aging, (c) persuade funding institutions and the public at large to support an end to the suffering and pain of aging, and (b) build a network of like-minded fellow travelers and advocates. These efforts are working, are beginning to pay off.

A great deal remains to be achieved, however. Senescent cells are just one of the important mechanisms of aging, and work on the others still requires various forms of aid, advocacy, unblocking. All of the real progress achieved to date in building a world in which rejuvenation is a possibility has been the result of philanthropy, the donations of thousands of supporters made to the SENS Research Foundation and Methuselah Foundation. These generous individuals funded the early stage research, the outreach, the hard work of patient advocacy. They helped to hold up the light, and that light brought the scientists and capital to found a new industry. Philanthropy works, demonstrably, to advance our society towards the medicine of rejuvenation - and it must continue to work if we are to benefit in our old age in the years ahead. So help to fund the work of the SENS Research Foundation when you consider where to place your charitable giving for 2020.

SENS Research Foundation 2020 Year End Fundraiser

2020 brought unprecedented challenges as a pandemic swept the globe, leaving more than a million dead and others isolated and fearful in their homes. Through all the updates on the sick and the dead, on testing and public health guidance, one constant remains: by far the greatest predictor of death from COVID-19 is age. Most of the co-morbidities that drive COVID severity are pathologies of aging. Flattening the "demographic curve" of degenerative aging would reduce the impact of COVID-19 to roughly that of an average recent flu season, while also reducing the staggering toll of age-related disease and death that continues to inflict suffering on humankind.

Ending that toll is our mission. At SENS Research Foundation, we develop rejuvenation biotechnologies: new therapies that will repair the accumulated cellular and molecular damage in our tissues and restore youthful function.

As we reflect on the past year, we're particularly grateful to the many donors whose steadfast commitment to our work endured through economic uncertainty, to those who have become SRF Patrons by pledging to support us with recurring donations, and to the new donors who have joined our cause. You've provided a steady income stream allowing SRF to continue to fight age-related disease during the uncertainty of 2020. We appreciate you more than we can say. We know you share our vision and passion for extending healthy lifespans.

With your support, we funded research establishing systems that may accelerate progress toward novel therapies against COVID-19 as well as lung and brain aging. With your support, we explored ways to address dementia by rejuvenating the neocortex. With your support, we fight hard to reverse aging by sponsoring research, educating new scientists, and providing outreach to the public and industry partners. With your support, we can break free of age-related disease. With your support, we can #UnlockLongevity together.

SENS Research Foundation's 2020 End of Year Fundraising Campaign runs through December 31st.

Why does physical exercise reduce cancer risk and improve cancer outcomes? Researchers here propose that the mechanism of interest involves an improved capacity for cell destruction on the part of cytotoxic T cells. Cancer is an age-related condition in large part because the efforts of the immune system are vital in cancer suppression, and because the immune system declines in effectiveness with age. Cancer incidence correlates very well with the age-related atrophy of the thymus, the organ responsible for maturation of T cells. The resulting reduction in the supply of naive T cells capable of tackling new threats, such as newly cancerous tissue, is harmful to health in later life.

Prior research has shown that physical activity can prevent unhealth as well as improve the prognosis of several diseases including various forms of cancer. Exactly how exercise exerts its protective effects against cancer is, however, still unknown, especially when it comes to the biological mechanisms. One plausible explanation is that physical activity activates the immune system and thereby bolsters the body's ability to prevent and inhibit cancer growth.

Researchers expanded on this hypothesis by examining how the immune system's cytotoxic T cells, that is white blood cells specialized in killing cancer cells, respond to exercise. They divided mice with cancer into two groups and let one group exercise regularly in a spinning wheel while the other remained inactive. The result showed that cancer growth slowed and mortality decreased in the trained animals compared with the untrained. Next, the researchers examined the importance of cytotoxic T cells by injecting antibodies that remove these T cells in both trained and untrained mice. The antibodies knocked out the positive effect of exercise on both cancer growth and survival, which according to the researchers demonstrates the significance of these T cells for exercise-induced suppression of cancer. The researchers also transferred cytotoxic T cells from trained to untrained mice with tumors, which improved their prospects compared with those who got cells from untrained animals.

To examine how exercise influenced cancer growth, the researchers isolated T cells, blood and tissue samples after a training sessions and measured levels of common metabolites that are produced in muscle and excreted into plasma at high levels during exertion. Some of these metabolites, such as lactate, altered the metabolism of the T cells and increased their activity. The researchers also found that T cells isolated from an exercised animal showed an altered metabolism compared to T cells from resting animals. In addition, the researchers examined how these metabolites change in response to exercise in humans. They took blood samples from eight healthy men after 30 minutes of intense cycling and noticed that the same training-induced metabolites were released in humans.

Link: https://news.ki.se/study-shows-how-exercise-stalls-cancer-growth-through-the-immune-system

Mouse models of Alzheimer's disease are quite artificial: mice, and indeed most mammals, do not naturally exhibit the relevant mechanisms underlying Alzheimer's disease, such as aggregation of amyloid-β. The details of the model become important in determining whether or not discoveries and interventions are relevant in anything other than the model. Thus one shouldn't become too excited by any small adjustment to cellular metabolism that appears to have profound effects on the progression of the condition in these models. Maybe it will be relevant to the human condition, but the odds are not good, looking at the history of this sort of thing. Still, the size of the effect in this case is quite interesting.

Researchers discovered that limiting the open time of a channel called the ryanodine receptor, which acts like a gateway to cells located in the heart and brain, reverses and prevents progression of Alzheimer's disease in animal models. A single RyR2 point mutation, which reduces RyR2 open time, prevents hyperexcitability, hyperactivity, memory impairment, neuronal cell death, and dendritic spine loss in an Alzheimer's disease mouse model.

Researchers also identified a drug, derived from the heart medication carvedilol, that interrupts the disease process by reducing the open type of the ryanodine receptor. The effect of giving the drug to animal models was remarkable: After one month of treatment, the memory loss and cognitive impairments in these models disappeared.

Previous research has shown that the progression of Alzheimer's disease is driven by a vicious cycle of the protein amyloid β (Aβ) inducing hyperactivity at the neuron level. However, the mechanism behind this wasn't fully understood nor were there effective treatments to stop the cycle. Here, the team used a portion of an existing drug used for heart patients, carvedilol, to treat mice models with Alzheimer's symptoms. "We treated them for a month and the effect was quite amazing. We couldn't tell the drug-treated disease models and the healthy models apart."

Link: https://libin.ucalgary.ca/news/research-team-discovers-breakthrough-potential-prevent-reverse-alzheimers