Fight Aging! Newsletter, April 6th 2020

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  • Genetic Variants Associated with Risk of Hypertension and Obesity also Correlate with Reduced Life Expectancy
  • ASC Specks in the Inflammatory Microglial Response to Amyloid-β Aggregation in Alzheimer's Disease
  • Transplanting Gut Microbes from Long-Lived Humans into Mice to Assess the Outcomes
  • The Longevity 2020 Online Conference, to be Held April 27th to May 1st 2020
  • Inhibition of ATM Kinase Reduces Cellular Senescence and SASP in Progeroid Mice
  • Chimeric Antigen Receptor Macrophages Instead of T Cells
  • Impaired Autophagy in the Aging of Stem Cell Populations
  • Downregulation of miR-155-5p Improves Mitochondrial Dynamics and Cell Function
  • Mesenchymal Stem Cell Extracellular Vesicles in Regenerative Medicine
  • Age-Slowing Interventions in the Context of Lung Aging
  • p53 in Cellular Senescence
  • Oral Administration of IAP Slows Aging in Mice by Reducing Gut Inflammation
  • Debating the Direction of Causation Between Physical Decline and Cognitive Decline in Aging
  • Fasting Accelerates Wound Healing in Mice
  • AQP1 and Cellular Senescence in the Aging of Tendons

Genetic Variants Associated with Risk of Hypertension and Obesity also Correlate with Reduced Life Expectancy

Identification of genetic variants associated with specific conditions has been a going concern for some time, but the creation of large national databases of genetic and biometric data in a number of countries has greatly expanded this area of study. In today's research materials, scientists demonstrate one way in which this can be used, as a confirmation of the importance of hypertension and obesity in present variations in human life expectancy. People with genetic variants that increase the odds of suffering either of these conditions tend to live shorter lives, something that also shows up in standard epidemiological studies.

Why is this the case? Hypertension, chronically increased blood pressure, results from the stiffening of blood vessels due to various low-level processes of cell and tissue damage. Cross-links that reduce elasticity in blood vessel walls, inflammation resulting from senescent cells, and so forth. The resulting increase in blood pressure leads to an acceleration of atherosclerosis, and pressure damage to delicate tissues in the kidneys, brain, and elsewhere. This is very harmful to organ function over the long term, as illustrated by the fact that even forcing a reduction in blood pressure, overriding regulatory mechanisms without addressing the underlying causes of the problem, can reduce mortality in old people.

The excess visceral fat of obesity, on the other hand, can be argued to accelerate the aging process by generating excessive numbers of senescent cells. This and other mechanisms in visceral fat tissue lead to greater levels of chronic inflammation, which in turn accelerates the development and progression of all of the common age-related conditions. Epidemiological studies suggest that any excess weight is harmful, but outright obesity is in the same ballpark as smoking when it comes to negative effects on health and life expectancy.

It's in our genome: Uncovering clues to longevity from human genetics

Part of DNA is composed of genes, of which proteins are produced that participate in virtually every process within our cells and organs. While variations in the genetic code determine biological traits, such as eye color, blood type, and risk for diseases, it is often a group of numerous variations with tiny effects that influence a phenotypic trait. Harnessing a huge amount of genetic and clinical data worldwide and a methodological breakthrough, it is now possible to identify individuals at several-fold increased risk of human diseases using genetic information.

Researchers have discovered that individuals who have a genetic susceptibility to certain traits, such as high blood pressure or obesity, have a shorter lifespan. To achieve their goal, the researchers analyzed genetic and clinical information of 700,000 individuals from biobanks in the UK, Finland and Japan. From these data, the researchers calculated polygenic risk scores, which are an estimate of genetic susceptibility to a biological trait, such as a risk for disease, to find out which risk factor causally influences lifespan.

The researchers found that high blood pressure and obesity were the two strongest risk factors that reduced lifespan of the current generation. Interestingly, while high blood pressure decreased lifespan across all populations the researchers investigated, obesity significantly reduced lifespan in individuals with European ancestry, suggesting that the Japanese population was somehow protected from the detrimental effects obesity has on lifespan.

Trans-biobank analysis with 676,000 individuals elucidates the association of polygenic risk scores of complex traits with human lifespan

While polygenic risk scores (PRSs) are poised to be translated into clinical practice through prediction of inborn health risks, a strategy to utilize genetics to prioritize modifiable risk factors driving heath outcome is warranted. To this end, we investigated the association of the genetic susceptibility to complex traits with human lifespan in collaboration with three worldwide biobanks (n = 675,898; BioBank Japan, UK Biobank, and FinnGen). In contrast to observational studies, in which discerning the cause-and-effect can be difficult, PRSs could help to identify the driver biomarkers affecting human lifespan.

A high systolic blood pressure PRS was trans-ethnically associated with a shorter lifespan (hazard ratio = 1.03) and parental lifespan (hazard ratio = 1.06). The obesity PRS showed distinct effects on lifespan in Japanese and European individuals. The causal effect of blood pressure and obesity on lifespan was further supported by Mendelian randomization studies. Beyond genotype-phenotype associations, our trans-biobank study offers a new value of PRSs in prioritization of risk factors that could be potential targets of medical treatment to improve population health.

ASC Specks in the Inflammatory Microglial Response to Amyloid-β Aggregation in Alzheimer's Disease

The Alzheimer's disease research community is nowadays ever more strongly considering chronic inflammation in the brain as a vital part of the progression of the condition. In the amyloid cascade hypothesis, a slow aggregation of amyloid-β over decades (for reasons that are debated) causes ever greater inflammatory dysfunction in microglia, the immune cells of the brain responsible for clearing up metabolic waste such as protein aggregates. That inflammation in turn sets the stage for tau aggregation to take place to a significant degree, causing cell death and severe neural dysfunction.

Today's open access research is an example of the sort of work taking place to better understand how amyloid-β interacts with microglia to produce the outcome of chronic inflammation. In principle at least, a better understanding usually leads to new targets for the development of drugs that can interfere in the process.

A great deal of hypothesizing takes place among Alzheimer's researchers. The animal models are highly artificial, and thus prone to misleading results, there is a great deal of dissatisfaction with the decades-long relentless focus on amyloid-β, and it is very costly to prove any particular point using human data and human patients. Theorizing is thus a great deal easier than validating any given hypothesis, and as a result there are are numerous variations on the basic idea that chronic inflammation is an important part of the progression of Alzheimer's disease. One faction sees rising levels of amyloid-β as only a side-effect of persistent infections (such as herpesvirus, lyme disease, and so forth), and it is the infection that produces lasting inflammation in brain tissue, and its downstream consequences. Another faction ties the new understanding of cellular senescence into the development of chronic inflammation in the brain. In the years ahead, these various views will eventually give way to a true understanding, as the state of the human evidence improves.

Alzheimer's disease: Inflammation triggers fatal cycle

Alzheimer's disease is characterized by clumps of the protein Aß (amyloid beta), which form large plaques in the brain. Aß resembles molecules on the surface of some bacteria. Over many millions of years, organisms have therefore developed defense mechanisms against such structures. These mechanisms are genetically determined and therefore belong to the so-called innate immune system. They usually result in certain scavenger cells absorbing and digesting the molecule.

In the brain, the microglia cells take over this role. In doing so, however, they trigger a devastating process that appears to be largely responsible for the development of dementia. On contact with Aß, certain molecule complexes, the inflammasomes, become active in the microglia cells. They then resemble a wheel with enzymes on the outside. These can activate immune messengers and thereby trigger an inflammation by directing additional immune cells to the site of action.

"Sometimes the microglia cells perish during this process. Then they release activated inflammasomes into their environment, the ASC specks." These released specks take on a calamitous dual role: On the one hand, they bind to the Aß proteins and make their degradation more difficult. On the other hand, they activate the inflammasomes in even more microglia cells, and much more than Aß alone would do. During this process, more and more ASC specks are released. It thus adds fuel to the fire, as it were, and thereby permanently stokes up the inflammation.

β-Amyloid Clustering around ASC Fibrils Boosts Its Toxicity in Microglia

Alzheimer's disease is the world's most common neurodegenerative disorder. It is associated with neuroinflammation involving activation of microglia by β-amyloid (Aβ) deposits. Based on previous studies showing apoptosis-associated speck-like protein containing a CARD (ASC) binding and cross-seeding extracellular Aβ, we investigate the propagation of ASC between primary microglia and the effects of ASC-Aβ composites on microglial inflammasomes and function. Indeed, ASC released by a pyroptotic cell can be functionally built into the neighboring microglia NOD-like receptor protein (NLRP3) inflammasome. Compared with protein-only application, exposure to ASC-Aβ composites amplifies the proinflammatory response, resulting in pyroptotic cell death, setting free functional ASC and inducing a feedforward stimulating vicious cycle. Clustering around ASC fibrils also compromises clearance of Aβ by microglia. Together, these data enable a closer look at the turning point from acute to chronic Aβ-related neuroinflammation through formation of ASC-Aβ composites.

Transplanting Gut Microbes from Long-Lived Humans into Mice to Assess the Outcomes

It is well known that the gut microbiome is influential on long-term health, and undergoes detrimental changes with advancing age. Beneficial species decline, while inflammatory and otherwise unhelpful species prosper. The reasons for these changes are not well understood, but probably involve a combination of many factors, such as diet, immune dysfunction, and so forth. There is a growing interest in the research community in assessing the contribution of gut microbiome changes to degenerative aging, and finding ways to reverse those changes.

The study noted here is less interesting for the presented data, and more interesting for demonstrating that one can in fact transplant gut microbes from a human to a mouse and expect to see results that mimic the quality of the human microbiome. Thus transplants from long-lived humans - with what is assessed via other measures to be a better, more youthful, more diverse gut microbiome - leads to healthier mice than is the case for transplants from an average older person with a more degraded gut microbiome. That this can be accomplished might lead to faster progress towards treatments that adjust the gut microbiome to a more beneficial state.

The most direct, blunt approach to therapy is some form of fecal microbiota transplant from young donor to old individual. In short-lived animal species, this resets the gut microbiome to a more youthful state and extends healthy life. In human medicine, fecal microbiota transplants are already carried out for severe conditions in which the gut is overtaken by pathological microbes. The challenges in implementation largely involve screening out undesirable microbes that a young donor can keep suppressed but an old recipient would struggle with. A possibly better approach would be a probiotic strategy of some sort, in which large volumes of desirable microbes are provided orally, encapsulated in a way that allows for their survival into the gut. These classes of therapy are close to practical realization, at present only lacking the will and the funding to move ahead.

Transplant of microbiota from long-living people to mice reduces aging-related indices and transfers beneficial bacteria

The interactions between gut microbiota and their host have become a popular topic in research. There is growing evidence to suggest that a close relationship exists between gut microbiota and aging. Age-related changes in gut microbiota occur widely among animals, with evidence of this ranging from insects to mammals. Human-based studies have revealed a trend in age-related microbiota features, which shows an increase in gut microbiota diversity from infants to adults, followed by a decrease as adults age. Researchers found signatures of extreme longevity in gut microbiota composition that were related to extreme aging. Others found 11 features shared among long-living Chinese and Italian people, including higher alpha diversity and operational taxonomic units (OTUs); they also showed that long-living people had greater gut microbiota diversity than a younger group among Chinese and Japanese populations.

High microbiota diversity has been associated with good health in general. Early research on the gut microbiota of elderly people has indicated that healthier subjects have significantly greater gut microbiota diversity than those in long-term residential care. Overall, the information obtained from studies such as these suggests that long-living people can serve as an acceptable model to investigate whether gut microbiota is a feasible target for promoting healthy aging. However, the exact roles that the microbiota play still require investigation.

Studies in animal subjects have shown that age-related microbiota can affect the lifespan of the host. Ten-day-old and 30-day-old Drosophila were used as microbiota donors for 10-day-old Drosophila. The lifespan of the 10-day-old transplant group lived significantly longer than the 30-day-old transplant group, and had a decreased frequency in intestinal barrier dysfunction. Subsequently, researchers transplanted the gut contents of young and old African turquoise killifish to old fish. Consistent with the results from Drosophila, fish transplanted with feces from young donors had a longer lifespan and were significantly more active. These results suggest that the gut microbiota of young individuals can slow host aging and prolong the lifespan of the tested species.

In the current study, the hypothesis that the gut microbiota of long-living people has the ability to delay host aging compared with those of average lifespan, is tested. To test this hypothesis, the gut microbiota of long-living (L group) and typical aging elderly people were transplanted into antibiotic-treated mice, which were then analyzed for differences in gut microbiota and aging indices. L group mice demonstrated greater microbiota diversity and beneficial bacteria, such as probiotic genera and short-chain fatty acid producers. Importantly, aging-related indices, such as lipofuscin and β-galactosidase accumulation, were less in the L group. Our experiment provided primary evidence that the gut microbiota of long-living people has the ability to delay host aging.

The Longevity 2020 Online Conference, to be Held April 27th to May 1st 2020

All of the longevity industry and gerontology conferences in coming months have been cancelled or rescheduled as a result of the present mix of COVID-19 pandemic and hysteria. An equal mix of both, perhaps. The best data to date puts the mortality rate at 0.66% or so, meaning about six yearly flu seasons worth of risk, and even that number is most likely still overstating the risk, as it misses the presently unknown count of infections that result in only minor symptoms. An article from earlier in the month on the uncertainties in all published numbers remains one of the more sane pieces written on the topic.

Still, when life hands you lemons, set up an online conference instead of merely mourning the end of gathering in person. So the Longevity.Technology team is assembling Longevity 2020, a four day online event of presentations for scientists, entrepreneurs, and investors in the longevity industry. The online conference will run from April 27th to May 1st, just four weeks away. Since the restrictions on productive economic activity look to last to the end of April at the very least in the US, we will all still have time on our hands by that point. If you have a company to pitch, research to present, or something sensible to say about human longevity and the treatment of aging as a medical condition, then it isn't too late to reach out and secure a place in the program.

Longevity 2020

You're at home. So are most of the experts in longevity. So, let's get together. Learn, share knowledge, build our networks, and take a break from Netflix. This difficult period will pass. It all begins with an idea. We're the team behind Longevity.Technology and, like you, we're disappointed that events have been cancelled, funding rounds postponed, and new knowledge is going unshared. So we thought: everyone's at home, even world experts, so let's get together and keep the Longevity sector on track. Boom.

We're using a new and interactive online events platform that enables you to interact with speakers directly, see full media presentations, meet with like-minded people, and build lasting relationships. Once we're happy that we have our killer programme of speakers and subjects we'll switch ticketing to live. Meanwhile, please pre-register so that you can stay updated: the button's up-top.

Defining Biological Aging

Addressing the need for candidate definitions from different, biological, clinical, logical and computational angles to adopt a consensus definition for biological aging. How are traditional biomarkers like body composition, muscle strength and cognition complimented by the techniques of methylation, inflammation, and epigenetics? With so many opinions and options: how can scientists prove their technologies and investors invest with confidence?

Rejuvenation Therapies

What progress is being made in senolytics, gene editing, immunotherapy, mitochondrial restoration, indication expansion, nutraceuticals, peptides, stem cells, and more? What companies are moving through the drug development pipeline towards in-human studies and ultimately the approval to market true rejuvenation therapies? With the toning-down of the '1000 year lifespan' rhetoric, there is growing confidence in the sciences of healthspan and lifespan: what should we expect within our lifetimes?

AI and Longevity

How is AI accelerating longevity and where: molecule identification, pre-clinical validation, digital health, lifestyle interventions, finance. With pre-clinical discovery reduced from months down to days, what are the implications for new longevity therapies in the new AI world? With apps directing us to live better and exercise more and people needing to live independently for longer - we explore the latest exciting AI applications.

Longevity Investing

It's all about growing the investment category: risk management, going public, investment platforms, emerging tech: 3D bioprinting, neuroceuticals, organ growth, agetech, and more. As markets are challenged by COVID-19 and investors run to safe havens, who are the key players in Longevity investing and where are they putting their money? The global longevity economy is projected to reach $27 trillion in 2026. With such a wide field, where are the market opportunities and which companies are innovating and disrupting?

Longevity: Start Now

What can you be doing to address your Longevity now: supplements, metformin, mTOR, NAD+, rapamycin, biohacking, fasting, biomarker tracking, monitoring apps. There are many pharmacological and non-pharmacological therapies that people talk about - but which ones show the most evidence in managing the hallmarks of aging? With many beginning to prescribe and self-prescribe drugs off-label - what are the risks and where is the proof of efficacy?

Inhibition of ATM Kinase Reduces Cellular Senescence and SASP in Progeroid Mice

Progeroid mice with DNA repair deficiencies exhibit an accelerated formation of senescent cells and manifestation of age-related conditions. This class of animal model has been used in research relating to cellular senescence in order to cost-effectively demonstrate that targeted removal of senescent cells is beneficial. However, one still needs to be careful when drawing conclusions based on their peculiar biochemistry. Progeria of this nature is quite unlike normal aging at the detail level.

Cells become senescent in response to reaching the Hayflick limit, tissue injury, molecular damage, or a toxic environment. A senescent cell ceases replication and generates senescence-associated secretory phenotype (SASP), a mix of signals that encourages both tissue remodeling and an immune response to destroy the senescent cell. In young people near all senescent cells are efficiently destroyed soon after their creation, but in older people senescent cells linger to cause chronic inflammation and tissue dysfunction.

A great deal of effort is going into deeper explorations of the biochemistry of cellular senescence these days. This is in no small part because any new discovery might have the potential to become a therapy that can treat numerous age-related conditions, and even aging itself, by alleviating the burden of senescent cells and their inflammatory, harmful signaling.

Researchers here identify an important regulator gene linking DNA damage with cellular senescence. Suppressing it in progeroid mice that exhibit high levels of DNA damage reduces markers of cellular senescence. However, it isn't clear that interfering in this process is a good idea. Removing or at least halting replication for cells with meaningful damage to their DNA is necessary to reduce the risk of cancer. Allowing damaged cells to continue replication is a poor strategy. It is far better to allow cells to become senescent in response to circumstances that carry an elevated risk of cancer, and then destroy them with periodic application of senolytic therapies.

ATM is a key driver of NF-κB-dependent DNA-damage-induced senescence, stem cell dysfunction and aging

DNA damage is known to increase with aging as demonstrated by an increase in DNA damage foci and oxidative DNA lesions. Intriguingly, persistent DNA damage response (DDR) signaling mediated by ATM activation has been reported to contribute to cellular senescence and the senescence-associated secretory phenotype (SASP). In vitro, SASP is dependent on ATM activation, suggesting a molecular link between ATM and NF-κB. However, it is still unclear if aberrant DNA damage-induced activation of ATM in vivo exacerbates the cellular stress response to increase NF-κB, senescence, SASP and subsequently aging.

To address the role of ATM in driving NF-κB mediated senescence and aging, we used Ercc1-/Δ mice that model a human progeroid syndrome caused by impaired repair of DNA damage. The mice express only 5% of the normal level of the DNA repair endonuclease ERCC1-XPF that is required for nucleotide excision, interstrand crosslink, and repair of some double-strand breaks. As a consequence, the Ercc1-/Δ mice spontaneously and rapidly develop progressive age-related diseases, including osteoporosis, sarcopenia, intervertebral disc degeneration, glomerulonephropathy, neurodegeneration, peripheral neuropathy, and loss of cognition.

Here, we demonstrate that ATM and downstream effectors are persistently elevated in Ercc1-/∆ and naturally aged mice, concomitant with hyperactive NF-κB signaling. Reducing ATM activity either genetically or pharmacologically reduced cellular senescence and downregulated NF-κB activation in cell culture. Importantly, Ercc1-/Δ mice heterozygous for Atm exhibited significantly reduced NF-κΒ activity, reduced cellular senescence, improved muscle-derived stem cell and progenitor cell function and attenuated age-related bone and intervertebral disc pathologies, leading to an extension of healthspan. Similarly, inhibiting ATM in Ercc1-/∆ mice by treatment with the ATM inhibitor KU-55933 reduced senescence and SASP marker expression. These results demonstrate a key role for ATM in aging and suggest that it is a therapeutic target for delaying or improving numerous age-related diseases.

Chimeric Antigen Receptor Macrophages Instead of T Cells

Chimeric antigen receptor T cell therapies have done well in the treatment of leukemias, and are being adapted for use with cancers that form solid tumors. A patient's own cells are engineered to bear a new synthetic receptor that matches a specific protein on the surface of cancerous cells, which encourages an effective immune response against the cancer. As researchers discuss here, an alternative to the continued use of T cells of the adaptive immune system is to apply chimeric antigen receptors to macrophages of the innate immune system instead.

Chimeric antigen receptor (CAR) T cell therapy has been a game-changer for blood cancers but has faced challenges in targeting solid tumors. Now researchers may have an alternative to T cell therapy that can overcome those challenges. Their research shows genetically engineering macrophages - an immune cell that eats invaders in the body - could be the key to unlocking cellular therapies that effectively target solid tumors. The approach in this study is closely related to CAR T cell therapy, in which patient immune cells are engineered to fight cancer, but it has some key differences. Most importantly, it centers around macrophages, which eat invading cells rather than targeting them for destruction the way T cells do.

Macrophages also have another key difference from T cells in that they are the body's first responders to viral infections. This has historically presented challenges in trying to engineer them to attack cancer, since macrophages are resistant to infection by the standard viral vectors used in gene and cell therapy. In fact, this anti-viral property carried another unexpected benefit. Macrophages are generally among the first cells to be drawn in by cancer, and they are exploited to help tumors instead of eating them. However, the research team showed that when the viral vector is inserted, not only do these engineered macrophages express the CAR, they also transform into highly inflammatory cells. This transformation allows macrophages to resist being co-opted by tumors. Researchers say CAR macrophages may also be able to stimulate the rest of the immune system as they attack, potentially opening the door to a greater immune response.

Impaired Autophagy in the Aging of Stem Cell Populations

The cellular housekeeping mechanisms of autophagy act to recycle proteins and structures within the cell. Upregulation of autophagy appears to be a crucial part of the reason why the response to mild stresses - such as heat, cold, lack of nutrients, and toxins - can actually improve cell and tissue function. Certainly the practice of calorie restriction relies upon functional autophagy in order to extend healthy life span. Researchers here note that autophagy is important in the maintenance of the many stem cell populations throughout the body that are required for ongoing tissue maintenance. The characteristic impairment of autophagy in later life, taking place for reasons that are only partially explored, may make a sizable contribution to the loss of stem cell function that also takes place with aging.

Autophagy is a fundamental cell survival mechanism that allows cells to adapt to metabolic stress through the degradation and recycling of intracellular components to generate macromolecular precursors and produce energy. The autophagy pathway is critical for development, maintaining cellular and tissue homeostasis, as well as immunity and prevention of human disease. Defects in autophagy have been attributed to cancer, neurodegeneration, muscle and heart disease, infectious disease, as well as aging. While autophagy has classically been viewed as a passive quality control and general house-keeping mechanism, emerging evidence demonstrates that autophagy is an active process that regulates the metabolic status of the cell.

Adult stem cells, which are long-lived cells that possess the unique ability to self-renew and differentiate into specialized cells throughout the body, have distinct metabolic requirements. Research in a variety of stem cell types have established that autophagy plays critical roles in stem cell quiescence, activation, differentiation, and self-renew. While it appears that targeting autophagy to inhibit the autophagy-mediated cell survival properties in cancer stem cells may hold promise for anti-cancer therapy, the importance of autophagy in maintaining normal stem cell function suggest that inducing autophagy may have therapeutic potential for regenerative medicine. Certainly within the context of aging, stimulation of autophagy via genetic and pharmacological approaches in aged stem cells have improved their regenerative capacity and function.

Downregulation of miR-155-5p Improves Mitochondrial Dynamics and Cell Function

Researchers here identify miR-155-5p as a potential target to improve mitochondrial function. This microRNA is upregulated with age, and appears to inhibit mitochondrial fission. That in turn prevents the cellular maintenance process of mitophagy from clearing out worn and damaged mitochondria efficiently enough to prevent loss of function. Since mitochondria provide the chemical energy store molecules that power all cellular operations, this has downstream consequences on cell and tissue function, including higher levels of cellular senescence.

Aging impairs the functions of human mesenchymal stem cells (MSCs), thereby severely reducing their beneficial effects on myocardial infarction (MI). MicroRNAs (miRNAs) play crucial roles in regulating the senescence of MSCs; however, the underlying mechanisms remain unclear. Here, we investigated the significance of miR-155-5p in regulating MSC senescence and whether inhibition of miR-155-5p could rejuvenate aged MSCs (AMSCs) to enhance their therapeutic efficacy for MI.

Young MSCs (YMSCs) and AMSCs were isolated from young and aged donors, respectively. The cellular senescence of MSCs was evaluated by senescence-associated β-galactosidase (SA-β-gal) staining. Compared with YMSCs, AMSCs exhibited increased cellular senescence as evidenced by increased SA-β-gal activity and decreased proliferative capacity and paracrine effects. The expression of miR-155-5p was much higher in both serum and MSCs from aged donors than young donors. Upregulation of miR-155-5p in YMSCs led to increased cellular senescence, whereas downregulation of miR-155-5p decreased AMSC senescence. Mechanistically, miR-155-5p inhibited mitochondrial fission and increased mitochondrial fusion in MSCs via the AMPK signaling pathway, thereby resulting in cellular senescence by repressing the expression of Cab39. These effects were partially reversed by treatment with AMPK activator or mitofusin2-specific siRNA.

By enhancing angiogenesis and promoting cell survival, transplantation of anti-miR-155-5p-AMSCs led to improved cardiac function in an aged mouse model of MI compared with transplantation of AMSCs. In summary, our study shows that miR-155-5p mediates MSC senescence by regulating the Cab39/AMPK signaling pathway and miR-155-5p is a novel target to rejuvenate AMSCs and enhance their cardioprotective effects.

Mesenchymal Stem Cell Extracellular Vesicles in Regenerative Medicine

Mesenchymal stem cell therapies vary widely in their ability to influence regeneration, though they fairly reliably reduce chronic inflammation in older patients. One challenge is that there is no standard on what constitutes a mesenchymal stem cell; it is a category so broad as to be almost meaningless. Further, two clinics performing what is ostensibly the same protocol using cells from the same source can produce widely divergent outcomes. In most cases, near all transplanted cells die, and the benefits obtained for the patient derive from signaling produced by the stem cells in the short period of survival following transplantation. A large fraction of this signaling is carried by extracellular vesicles, and since these vesicles can be harvested and used for therapy more readily than is the case for cells, many researchers and clinicians are turning their focus towards vesicle-based treatments.

Surprisingly, patients inoculated with mesenchymal stem cells (MSCs) to promote tissue regeneration showed less than 1% of such cells in the damaged tissue after 1 week. Yet, paradoxically, such strategy has produced positive results in the treatment of several pathologies, favoring tissue regeneration and functionality. Therefore, it has been suggested that the regenerative effect of the MSC is not mainly due to their capacity to proliferate and differentiate into the required cellular types in the damaged tissue. Instead, their main functionality would stem from their paracrine actions, through the production of different factors.

Interestingly, such hypothesis is supported by several studies, demonstrating that conditioned media from MSC cultures have a similar regenerative capacity - or even higher - than the MSC themselves. For instance, that has been demonstrated in rodent models of acute myocardial infarction. These results demonstrate the surprising therapeutic relevance of the MSC secretome. In view of these results, it has been proposed to rename such stem cells as "medicinal signaling cells."

The secretome of the MSC has one free fraction, made of soluble factors and metabolites, as well as other encapsulated into microvesicles (MV), to which the extracellular vesicles (EV) belong. Interestingly, it has been found that the latter is the main responsible for the therapeutic properties of the conditioned media from MSC cultures. This way, those EV can regulate different physiological processes, like cellular proliferation, differentiation, and migration. The therapeutic features of the MSC EV are mainly due to their immunomodulatory and immunosuppressive activities.

The use of EVs in therapy has relevant advantages, in relation to MSCs. Among them are the following: (i) can be isolated and stored at low temperatures, until needed, without requiring the production of large amounts of cells at the time of inoculation, which is needed for cellular therapy; (ii) their contents are encapsulated and protected from degradation in vivo (preventing some of the problems associated with small soluble molecules, such as cytokines, growth factors, transcription factors, and RNA, which are rapidly degraded); (iii) are quite stable, exhibiting a long average life; (iv) can be intravenously injected, reaching distant places, since the vesicles are small and circulate readily, whereas the MSC are too large, and thus may have difficulty circulating through thin capillaries; (v) can pass through the blood-brain barrier; and (vi) have reduced risks of unwanted side-effects, such as immune rejection.

Age-Slowing Interventions in the Context of Lung Aging

Researchers here consider a very conservative set of interventions known to modestly slow the progression of aging in laboratory species, largely by altering metabolism to upregulate beneficial cellular stress responses. The researchers look through the lens of lung aging, specifically, reviewing the evidence for these therapies to slow the deterioration in lung function and onset of lung disease in older individuals, or to be the basis for treating established lung disease.

To date, the most reliable, best-researched way to extend life span is through the practice of calorie restriction (CR), which involves reducing calorie intake while simultaneously maintaining good nutritional status. Although the effects of diet on lung aging per se has thus far been rarely studied, several studies suggest a significant role of dietary modulation on lung aging. When a study examined the effects of aging on lung epithelial cells and stem cells and the effect of CR on young and old lungs, CR was identified to induce several potentially beneficial changes in lung epithelial cells, even when it is initiated at an older age, including reversal of some aging-induced changes.

The growth hormone/IGF axis can be manipulated in animal models to promote longevity; IGF-related proteins have also been implicated in risk of aging-associated diseases in humans. Indeed, a recent study which evaluated lung function parameters in a large cohort of patients with acromegaly due to excess growth hormone, revealed that these patients showed signs of small airway obstruction. However, the idea of inhibiting the growth hormone/IGF-I axis for the management of chronic obstructive pulmonary disease (COPD) may not be straightforward. Previously, there were attempts to use recombinant human growth hormone treatment which has been proposed to improve nitrogen balance and to increase muscle strength in patients with COPD, although significant beneficial effects were not observed.

A series of studies showed that mTOR inhibitor rapamycin extended lifespan in yeast, nematodes, fruit flies and mice, firmly establishing mTOR signaling as a central, evolutionarily conserved regulator of longevity. Aging may affect adaptive responses to stress decreasing autophagy through activation of mTORC1 in lung fibroblasts, and this mTOR activation may contribute to the resistance to cell death in idiopathic pulmonary fibrosis (IPF) lung fibroblasts. In addition, a recent metaanalysis of genome-wide studies across three independent cohorts reported the importance of mTOR signaling in lung fibrosis.

Sirtuins (SIRTs) are well-known mediators of aging. Suppression of cellular senescence by SIRTs is mainly mediated through delaying age-related telomere attrition, sustaining genome integrity and promotion of DNA damage repair. A study suggested that accelerated epithelial senescence which can be antagonized by SIRT6 might play a role in IPF pathogenesis through perpetuating abnormal epithelial-mesenchymal interactions. When the mRNA and protein levels of all seven known sirtuins (SIRT1-7) were assessed in primary lung fibroblasts from patients with IPF and systemic sclerosis-associated interstitial lung disease in comparison with lung fibroblasts from healthy controls, these unbiased tests revealed a tendency for all SIRTs to be expressed at lower levels in fibroblasts from patients compared with controls, but the greatest decrease was observed with SIRT7.

Metformin has been shown to increase lifespan and delay the onset of age-associated decline in several experimental models. In a bleomycin model of lung fibrosis in mice, metformin therapeutically accelerated the resolution of well-established fibrosis in an AMPK-dependent manner, further supporting a role for metformin to reverse established fibrosis by facilitating deactivation and apoptosis of myofibroblasts.

An age-associated increase in chronic, low-grade sterile inflammation termed "inflammaging" is a characteristic feature of mammalian aging that shows a strong association with occurrence of various age-associated diseases. Although it is not clearly defined whether the pulmonary environment becomes inflammatory with increasing age in humans, an in vivo study using a murine model organism suggests this possibility. The lungs of old mice have elevated levels of proinflammatory cytokines and a resident population of highly activated pulmonary macrophages.

p53 in Cellular Senescence

Cellular senescence is one of the contributing causes of aging, in the sense that senescent cells accumulate in old tissues. Even when only a tiny fraction of all cells are senescent, their signaling causes chronic inflammation and disruption of tissue function. Senescence is, however, a helpful program when these cells exist only temporarily and are promptly destroyed. The signaling that is so harmful when maintained over the long term aids in wound healing and suppression of cancer when present for a short time only. Since the comparatively recent acceptance of senescent cells as an important cause of aging, the research community has spent a great deal of effort in better understanding the biochemistry of cellular senescence. The open access paper here is a representative example of the output of these scientific initiatives.

The classical depiction of senescence as a static, uniform, and irreversible cellular state has been progressively reconsidered, and senescence is now envisioned as a dynamic and multistep process. During the initiation of the senescence, which is also called as "primary senescence", the stressed cells may be still able to repair and/or eliminate the cause of the damage and then can escape from cell cycle arrest. For example, it was demonstrated that a small proportion of senescent embryonic fibroblasts were capable of reentering the cell cycle when p53 expression was suppressed through RNA interference.

However, these rare cases are considered to take place only in the early stage of senescence establishment. Moreover, persistent exposure to a damaging environment leads the cells to the next stage of senescence, known as "developing senescence", where cells are poised to demonstrate full-featured senescence. Nevertheless, if senescent conditions continue for extended periods of time, as it happens, for instance, in the aging process, the cells enter a third phase of senescence, known as "late senescence", in which they may be characterized by heterogeneous phenotypes such as flattened and enlarged cell shape, expanded lysosomal compartment and vacuoles, increased metabolic rate and reactive oxygen species (ROS) production, senescence-associated secretory phenotype (SASP) secretion.

In most of the models studying senescent cells, p53 (as well as the DNA damage response proteins) seems to be involved in the earlier stages, and the time factor plays an important role in the entire process. p53 activity decreases with time, and this is consistent with the idea of p53 (and p21cip1) being a crucial factor for the induction of the senescence and a gate to an early phase and still reversible senescence. On the other hand, the subsequent increase of p16 activity would be responsible for a late senescent state characterized by a distinct and permanent senescence phenotype, which is no longer reversible through p53 inhibition.

Oral Administration of IAP Slows Aging in Mice by Reducing Gut Inflammation

The work here might be taken as an indication of the importance to aging of chronic inflammation and breakdown of the intestinal barrier generated in part by changes in the gut microbiome. Oral supplementation with the enzyme intestinal alkaline phosphatase (IAP) reduces both of these issues, and the result is mice that exhibit a slowed aging and lesser degrees of age-related frailty.

It's now accepted that gut-barrier dysfunction and gut-derived chronic inflammation play a role in human aging, but how that process is regulated is still largely a mystery. Studying mice and fruitflies, researchers found that the enzyme intestinal alkaline phosphatase (IAP) helped prevent intestinal permeability and gut-derived systemic inflammation, resulting in less frailty and extended life span. "Oral IAP supplementation in older mice significantly preserved gut barrier function and was associated with preserving the homeostasis of the gut microbiota during aging. In other words, the enzyme maintained the composition of the gut bacteria and controlled the low-grade chronic inflammation that can happen with aging."

Because the scientists were using animal models, they were able to test blood from the portal venous system, which goes from the GI tract into the liver and then on through the rest of the body. This gave a more direct measure of what is passing across the gut barrier than blood from a human arm would provide. Previous research suggests that IAP blocks an endotoxin called lipopolysaccharide (LPS). Because IAP is a naturally occurring enzyme that almost entirely remains in the gut rather than traveling throughout the system, researchers believe it should prove nontoxic to humans, and those who are found to have low levels, especially as they age, will simply be able to supplement.

Debating the Direction of Causation Between Physical Decline and Cognitive Decline in Aging

Researchers here suggest that the direction of causation between physical decline and cognitive decline is largely the opposite of the present consensus. Most of the evidence of recent decades points to physical decline, and associated lack of activity, having a negative impact the brain. Certainly there are any number of studies showing exercise to have a beneficial effect on cognitive function. Here, however, researchers propose that declines in cognitive function lead the declines in physical function in aging.

Someone dies somewhere in the world every 10 seconds owing to physical inactivity - 3.2 million people a year. From the age of 50, there is a gradual decline not just in physical activity but also in cognitive abilities since the two are correlated. But which of them influences the other? Does physical activity impact on the brain or is it the other way around?

"Correlations have been established between these two factors, particularly in terms of memory, but also regarding the growth and survival of new neurons. But we have never yet formally tested which comes first: does physical activity prevent a decline in cognitive skills or vice versa? That's what we wanted to verify. Earlier studies based on the correlation between physical activity and cognitive skills postulated that the former prevent the decline of the latter. But what if this research only told half the story? That's what recent studies suggest, since they demonstrate that our brain is involved when it comes to engaging in physical activity."

Researchers tested the two possible options formally using data from the SHARE survey (Survey of Health, Aging and Retirement in Europe), a European-wide socio-economic database covering over 25 countries. The cognitive abilities and level of physical activity of 105,206 adults aged 50 to 90 were tested every two years over a 12-year period. Researchers employed this data in three separate statistical models. In the first, they looked at whether physical activity predicted the change in cognitive skills over time; in the second, whether cognitive skills predicted the change in physical activity; and in the third, they tested the two possibilities bidirectionally.

The researchers found that the second model adjusted the most precisely to the data of the participants. The study demonstrates, therefore, that cognitive capacities mainly influence physical activity and not vice versa, as the literature to date had postulated. "Obviously, it's a virtuous cycle, since physical activity also influences our cognitive capacities. But, in light of these new findings, it does so to a lesser extent."

Fasting Accelerates Wound Healing in Mice

This study delves into the mechanisms by which a short period of fasting can accelerate wound healing. Fasting triggers many of the same cellular stress responses, such as upregulated autophagy, as occur during the practice of calorie restriction. It isn't exactly the same, however, so it is always worth asking whether any specific biochemistry observed in either case does in fact occur in both situations. In particular, the period of refeeding following fasting appears to have beneficial effects that are distinct from those that occur while food is restricted.

Multiple forms of therapeutic fasting have been reported regarding their efficacy to improve health (decreasing body fat and blood pressure, promoting stem cell function and regeneration, reversing immunosuppression, suppressing inflammation, etc.), delay aging and extend life span. Recently, it was shown that fasting for 48 h during a 4-day observation period after stroke was able to augment angiogenesis in ischemic brain and alleviate cerebral ischemic injury in mice; periodic fasting (a 48-hour period of fasting per week for one month) resulted in reduced cortical atrophy and long-term neurobehavioral improvement. Nonetheless, the regulatory molecular mechanism by which fasting affects angiogenesis still remains unclear.

Here, we generated full-thickness excisional or burn skin wounds in streptozotocin-induced diabetic mice and normal mice, respectively, and determined whether fasting prior to or after wound injury for a certain period of time can promote angiogenesis and speed up the process of wound healing. In vitro, we evaluated the effects of fasting and refeeding on the proliferation, migration and angiogenic tube formation of endothelial cells. To further explore the molecular mechanism, transcriptome sequencing of fasting and non-fasting endothelial cells was conducted to screen the differentially expressed angiogenesis-related genes and the role of the candidate genes in the fasting-induced promotion of angiogenesis was demonstrated.

Two times of 24-h fasting in a week after but especially before wound injury efficiently induced faster wound closure, better epidermal and dermal regeneration, less scar formation and higher level of angiogenesis in mice with diabetic or burn wounds. Transcriptome sequencing revealed that fasting itself, but not the following refeeding, induced a prominent upregulation of a variety of pro-angiogenic genes, including SMOC1 and SCG2. Immunofluorescent staining confirmed the increase of SMOC1 and SCG2 expression in both diabetic and burn wounds after fasting treatment. When the expression of SMOC1 or SCG2 was down-regulated, the fasting/refeeding-induced pro-angiogenic effects were markedly attenuated.

AQP1 and Cellular Senescence in the Aging of Tendons

Researchers here show that declining expression of the aquaporin AQP1 influences the age-related increase in cellular senescence in tendon stem cells and progenitor cells. Since the more general acceptance in the research community of senescent cell accumulation as an important cause of degenerative aging, there has been an increased interest in deeper investigations of the biochemistry of cellular senescence. It isn't clear that preventing cells from becoming senescent is always going to be beneficial, however. Does the method of prevention work by reducing cell damage and dysfunction that provokes senescence, which is a good thing, or does it work by holding back senescence in damaged and dysfunctional cells? That latter option may cause more problems than it solves.

Previous studies have demonstrated that tendon aging is closely associated with the functional changes of tendon stem/progenitor cells (TSPCs). TSPCs express classical stem cell markers and typical tendon-lineage genes. Studies have demonstrated the vital role of TSPCs in tendon repair, regeneration, and homeostasis maintaining. However, TSPCs premature entry into senescence during tendon aging, senescent TSPCs exhibit reduced self-renewal, migration, and tenogenic differentiation capacity compared with young cells, and these age-related changes in TSPCs would impair tendon healing and regeneration capacity.

Aquaporins (AQPs) are a family of small water-transporting membrane proteins. Previous studies also indicated that AQP1 is involved in tissue aging. In aged skin tissue, AQP1 level was decreased, which might be correlated with aging-related skin dryness. In addition, recent studies have indicated that AQP1 is also involved in the regulation of stem cells. Although studies have indicated the important role of AQP1 in tissue aging and regulation of stem cell, there were no studies focused on the role of AQP1 in TSPCs senescence.

In the present study, we investigated the AQP1 expression profile of TSPCs isolated from rats at different ages. We demonstrated that AQP1 expression declines with age in TSPCs, and AQP1 plays a vital role in TSPCs senescence. Decreased AQP1 was associated with activation of JAK-STAT signaling pathways in aged TSPCs. Furthermore, overexpression of AQP1 restored the age-related reduction of self-renewal, migration, and tenogenic differentiation in TSPCs. Our results collectively indicated that AQP1 could be an ideal target for antagonizing tendon aging.


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