Fight Aging! Newsletter, August 3rd 2020

Ageing phenotypes, such as years lived in good health (healthspan), total years lived (lifespan), and survival until an exceptional old age (longevity), are of interest to us all but require exceptionally large sample sizes to study genetically. Here we combine existing genome-wide association summary statistics for healthspan, parental lifespan, and longevity in a multivariate framework, increasing statistical power, and identify 10 genomic loci which influence all three phenotypes.

The effects of loci of interest on male and female lifespan are largely the same, although their effect on survival may be slightly stronger in middle age (40-60 years) compared to old age (older than 80 years). We find these loci of interest colocalise with the expression of 28 cis-genes and 50 trans-genes, some of which are known to become differentially expressed with increasing age. Lastly, we find these genes are enriched for seven hallmark gene sets (particularly haem metabolism) and 32 largely overlapping biological pathways (including apoptosis and homeostasis), and in line with the highlighted pathways, we find a causal role for iron levels in healthy life.

Haem synthesis declines with age and its deficiency leads to iron accumulation, oxidative stress, and mitochondrial dysfunction. In turn, iron accumulation helps pathogens to sustain an infection, which is in line with the known increase in infection susceptibility with age. In the brain, abnormal iron homeostasis is commonly seen in neurodegenerative diseases such as Alzheimer's and Parkinson's disease and multiple sclerosis. Plasma ferritin concentration, a proxy for iron accumulation when unadjusted for plasma iron levels, has been associated with premature mortality in observational studies, and has been linked to liver disease, osteoarthritis, and systemic inflammation.

Alzheimer's disease is a progressive disorder in which the nerve cells (neurons) in a person's brain and the connections among them degenerate slowly, causing severe memory loss, intellectual deficiencies, and deterioration in motor skills and communication. One of the main causes of Alzheimer's is the accumulation of a protein called amyloid β (Aβ) in clusters around neurons in the brain, which hampers their activity and triggers their degeneration.

Studies in animal models have found that increasing the aggregation of Aβ in the hippocampus - the brain's main learning and memory center - causes a decline in the signal transmission potential of the neurons therein. This degeneration affects a specific trait of the neurons, called synaptic plasticity, which is the ability of synapses (the site of signal exchange between neurons) to adapt to an increase or decrease in signaling activity over time. Synaptic plasticity is crucial to the development of learning and cognitive functions in the hippocampus. Thus, Aβ and its role in causing cognitive memory and deficits have been the focus of most research aimed at finding treatments for Alzheimer's.

Researchers first perfused slices of the mouse hippocampus with Aβ to confirm that Aβ causes the signaling abilities of neurons in the slices to decline, impairing synaptic plasticity. Upon additional perfusion with oxytocin, however, the signaling abilities increased, suggesting that oxytocin can reverse the impairment of synaptic plasticity that Aβ causes. In a normal brain, oxytocin acts by binding with special structures in the membranes of brain cells, called oxytocin receptors. Expectedly, when the receptors were blocked, oxytocin could not reverse the effect of Aβ, which shows that these receptors are essential for oxytocin to act.

Oxytocin is known to facilitate certain cellular chemical activities that are important in strengthening neuronal signaling potential and formation of memories, such as influx of calcium ions. Previous studies have suspected that Aβ suppresses some of these chemical activities. When the scientists artificially blocked these chemical activities, they found that addition of oxytocin addition to the hippocampal slices did not reverse the damage to synaptic plasticity caused by Aβ. Additionally, they found that oxytocin itself does not have any effect on synaptic plasticity in the hippocampus, but it is somehow able to reverse the ill-effects of Aβ.

Oxytocin, a peptide hormone synthesized in the hypothalamic paraventricular nucleus, has been reported to participate in the regulation of learning and memory performance. However, no report has demonstrated the effect of oxytocin on the amyloid-beta (Aβ)-induced impairment of synaptic plasticity. In this study, we examined the effects of oxytocin on the Aβ-induced impairment of synaptic plasticity in mice.

To investigate the effect of oxytocin on synaptic plasticity, we prepared acute hippocampal slices for extracellular recording and assessed long-term potentiation (LTP) with perfusion of the Aβ active fragment (Aβ25-35) in the absence and presence of oxytocin. We found that oxytocin reversed the impairment of LTP induced by Aβ25-35 perfusion in the mouse hippocampus. These effects were blocked by pretreatment with the selective oxytocin receptor antagonist L-368,899. Furthermore, the treatment with the ERK inhibitor U0126 and selective Ca2+-permeable AMPA receptor antagonist NASPM completely antagonized the effects of oxytocin.

Previous studies on the protection of alcoholic beverages have been primarily focused on the polyphenols such as resveratrol, procyanidins and other substances like catechin and tannin. Ironically, the most important common component of all alcoholic beverages, alcohol or ethanol, has received much less attention. In this study, we use ethanol, the common substance in all kinds of alcoholic beverages, as a single variable to explore its effects in vivo. Our data showed that the long-term 3.5% ethanol substitution for drinking water had beneficial effects in mice, the daily performance of ethanol-fed mice was enhanced, the athletic ability and healthspan of ethanol-fed mice drastically improved. Furthermore, the ethanol-fed mice showed the resistance to high-fat diet (HFD). When supplemented with 3.5% ethanol, the HFD mice showed reduced multiple organ pathogenicity, increased insulin sensitivity, and decreased NF-kB activation and inflammatory cytokines. These changes caused by ethanol are astonishing and impressive.

It has been well accepted that acute and chronic excessive alcohol exposure is conducive to tissue injury. However, one should be mindful that the injuries caused by the excessive use of alcohol are dose-dependent. In our study, the long term 3.5% ethanol-fed mice did not show the common negative effects of alcohol. At this dose, we did not observe any pathological structural changes in the liver, the heart, or the kidneys; neither did we detect any impairments of learning, memory, and cognition by the water maze.

One of the pathophysiological mechanisms induced by alcohol abuse has been identified as mitochondrial dysfunction. On the other hand, the mitochondrial volume was associated with high levels of physical activity. The improved mitochondrial function of long-term low-dose ethanol-intake (LLE) mice may be due to their high level of daily physical activity and enhancement of athletic ability of LLE mice. In our experiments, we observed that the mitochondrial density in the liver and the skeletal muscles of the ethanol-fed group increased, and the morphology became stronger with more cristae, indicating improved mitochondrial function under the moderate ethanol feeding.

AMPK induces mitochondrial biogenesis and has emerging roles in the regulation of both mitochondrial metabolism and dynamics. Phosphorylation activity of AMPK, necessary for mitochondrial biogenesis via SIRT1 and PGC1a, was increased in the liver of the LLE mice. Considering the activation of AMPK by moderate ethanol intake, it seems reasonable to entertain the hypothesis that the rapid acetate metabolism following the ingestion of ethanol generates sufficient AMP to transiently activate AMPK, which in turn induces the synthesis of certain long-lived proteins that act to boost insulin sensitivity and possibly aid the efficiency of fat oxidation as well.

Natural selection has shaped a large variation of lifespan across mammals, with maximum lifespan ranging from a few months (e.g. short-lived shrews) to 211 years (e.g. bowhead whale). Although the bowhead whale is exceptionally long-lived, its lifespan is arguably not as extreme as that of a 30 years old naked mole-rat given their body sizes, as maximum lifespan (MLS) exhibits a positive correlation with body size within mammals. Thus, lifespan comparison across mammals requires body size correction. To resolve this, the longevity quotient (LQ) was introduced, which is defined as the ratio of observed lifespan to predicted lifespan for a non-flying mammal of the same body size. Using this approach bats are the longevity extremists, with some species living up to ten times longer than expected given their body size. The Brandt's bat (Myotis brandtii) holds the record for longevity, with a maximum lifespan of more than 40 years, living 8-10 times longer than expected given a body weight of ~7 grams. This renders bats as one of the most ideal taxa to explore the molecular basis of extraordinary longevity in mammals.

Although the majority of bat species are long-lived, especially within the Myotis genus, there are a few short-lived exceptions, such as the velvety free-tailed bat (Molossus molossus) and the evening bat (Nycticeius humeralis), living as long as would be expected given their body size. A recent study has suggested that the ancestral bat lived up to 2.6 times longer than expected given body size, indicating that the extreme longevity observed in the longest-lived bat genera may have evolved multiple times. This also suggests that short-lived bat species may have lost their longevity adaptations. Therefore, this wide range of lifespans observed in bats enables us to utilize comparative evolutionary approaches to search for genetic differences within closely-related long- and short-lived bat species.

In this study we performed a comparative genomic and transcriptomic analysis between long-lived Myotis myotis (MLS = 37.1 years; LQ = 5.71) and short-lived Molossus molossus (MLS = 5.6 years; LQ = 0.99) to ascertain the molecular signatures associated with longevity in bats. Based on the genome-wide alignments of single-copy orthologous genes between these two species, we detected and further investigated the genes that were fast-evolving and showed significant positive selection. We also deep sequenced blood transcriptomes from eight adult individuals for each species, and explored the genes and pathways that were differentially expressed. To ascertain if long-lived bats have evolved a transcriptomic signature of longevity, we further investigated the expression of 'pro'- and 'anti'-longevity genes in the blood transcriptomes of M. myotis and M. molossus. Although the majority of genes underwent purifying selection, we observed a significant transcriptional alteration between these two species.

Among 2,086 genes that exhibited large interspecific expression variation, the genes that showed higher expression in long-lived M. myotis were mainly enriched in DNA repair and autophagy. Further pathway analysis suggested that six biological processes, including autophagy, were differentially expressed between M. myotis and M. molossus. We also show that M. myotis had significantly lower expression levels of anti-longevity genes, suggestive of a transcriptomic signature of longevity naturally evolved in long-lived bats. Together with the previous findings in other long-lived mammals, our study implies that enhanced DNA repair and autophagy activity may represent a universal mechanism to achieve longevity in long-lived mammals.

Aubrey is a plain-speaking biomedical gerontologist who is committed to combating the aging process. We started by asking him about what he was up to at the moment.

SENS Research Foundation suffered a fair amount of slowdown as a result of the pandemic, but we're picking up now. I think the most exciting thing we're doing is continuing to strengthen the pipeline between the really early-stage translational work we do at SENS and the "just investable" stage work pursued by startups in our space, including our own spinouts. Basically, the appetite of some investors is increasingly emphasising projects that are so early that they would historically be viewed as pre-competitive; that boundary is now becoming very blurred.

What isn't getting sufficient exposure?

I would say that the single biggest elephant in the room is the simultaneous administration of multiple therapies. It is subliminally understood that damage repair is the future of longevity medicine, and also that the damage repair paradigm is inescapably a divide-and-conquer one that will entail combination therapies, but the medical industry is really not set up to develop and promote that way of working. At some point that has to change, and I'm hopeful that investors at the more courageous end of the spectrum will soon find ways to start that process in earnest.

Our survey found that most investors appear to prefer seed-to-early-stage investing, have you found this to be case in your networks?

Absolutely. At this point I don't see how things could be otherwise, actually, because the investment opportunities consist almost entirely of startups, which in turn is because the underlying technologies are so new.

We also saw that senolytics are a very popular category for investors - are you seeing an increased appetite from investors?

I do see that tendency too, and it's not surprising to me, because senolytics have two huge things going for them: they are bona fide rejuvenators (i.e. they repair a type of aging damage rather than just slowing down its accumulation), which is much more exciting to people old enough to have money to invest, and they are only just now going into clinical trials and showing impressive results, so they are opportunities for first movers.

Scientists have demonstrated that age-related hearing loss, also called presbycusis, is mainly caused by damage to hair cells, the sensory cells in the inner ear that transform sound-induced vibrations into the electrical signals that are relayed to the brain by the auditory nerve. Their research challenges the prevailing view of the last 60 years that age-related hearing loss is mainly driven by damage to the stria vascularis, the cellular "battery" that powers the hair cell's mechanical-to-electrical signal conversion.

Researchers examined 120 inner ears collected at autopsy. They compared data on the survival of hair cells, nerve fibers, and the stria vascularis with the patients' audiograms to uncover the main predictor of the hearing loss in this aging population. They found that the degree and location of hair cell death predicted the severity and pattern of the hearing loss, while stria vascularis damage did not. Previous studies examined fewer ears, rarely attempted to combine data across cases and typically applied less quantitative approaches. Most importantly, prior studies greatly underestimated the loss of hair cells, because they didn't use the state-of-the art microscopy techniques.

Previous animal studies suggested that presbycusis is caused by atrophy of the stria vascularis, a highly vascularized cluster of ion-pumping cells, located in the inner ear adjacent to the hair cells. The stria serves as a "battery" that powers the hair cells as they transform sound-evoked mechanical motions into electrical signals. In aging laboratory animals, such as gerbil, there is very little loss of hair cells, compared to humans, even at the end of life. However, there is prominent damage to the stria vascularis, and damage to the stria will, indeed, cause hearing loss. Prior to this new study, most scientists have assumed that the aging gerbil data also apply to human presbycusis.

The researchers say the new findings are good news given recent progress in the development of therapies to regenerate missing hair cells. If presbycusis were due primarily to strial damage, hair cell regeneration therapy would not be effective. This new study turns the tables, suggesting, that vast numbers of hearing impaired elderly patients could likely benefit from these new therapies as they come to the clinics, hopefully within the next decade.

A strong cellular lining is essential for a healthy gut as it provides a barrier to the billions of microbes and harmful toxins present in our intestinal tract. This barrier is often damaged by infection and inflammation, which causes many painful symptoms. Researchers investigated the environment that surrounds gut stem cells and used "mini gut" organoid methodology where tiny replicas of gut tissue were grown in a dish. The study defined key cells that reside in close proximity to stem cells in the gut that produce the biomolecule Neuregulin-1 (NRG1) that acts directly on stem cells to kick-start the repair process.

"Our really important discovery is that supplementation with additional Neuregulin-1 accelerates repair of the gut lining by activation of key growth pathways. Our findings open new avenues for the development of Neuregulin 1-based therapies for enhancing intestinal repair and supporting rapid restoration of the critical gut function."

Gastrointestinal disease, such as Crohn's disease and ulcerative colitis, is a major health issue worldwide and results in severe damage to the epithelial cell layer lining the gut. Under these conditions, the intestine has a limited capacity to repair efficiently to restore its main absorptive function and is associated with symptoms including diarrhoea, dehydration, loss of weight and malnutrition. Developing ways to support intestinal tissue repair will dramatically improve patient recovery.

Aging in the epidermis is marked by a gradual decline in barrier function, impaired wound healing, hair loss, and an increased risk of cancer. This could be due to age-related changes in the properties of epidermal stem cells and defective interactions with their microenvironment. Currently, no biochemical tools are available to detect and evaluate the aging of epidermal stem cells.

Cellular glycosylation is involved in cell-cell communications and cell-matrix adhesions in various physiological and pathological conditions. Here, we explored the changes of glycans in epidermal stem cells as a potential biomarker of aging. Using lectin microarray, we performed a comprehensive glycan profiling of freshly isolated epidermal stem cells from young and old mouse skin. Epidermal stem cells exhibited a significant difference in glycan profiles between young and old mice. In particular, the binding of a mannose-binder rHeltuba was decreased in old epidermal stem cells, whereas that of an α2-3Sia-binder rGal8N increased.

These glycan changes were accompanied by upregulation of sialyltransferase, St3gal2, and St6gal1 and mannosidase Man1a genes in old epidermal stem cells. The modification of cell surface glycans by overexpressing these glycogenes leads to a defect in the regenerative ability of epidermal stem cells in culture. Hence, our study suggests the age-related global alterations in cellular glycosylation patterns and its potential contribution to the stem cell function. These glycan modifications may serve as molecular markers for aging, and further functional studies will lead us to a better understanding of the process of skin aging.

Glucosamine is a non-vitamin, non-mineral specialty supplement commonly used to manage osteoarthritis and joint pain. Although the effectiveness of glucosamine supplementation for osteoarthritis and joint pain remains controversial, several human, animal, and laboratory studies have suggested that glucosamine may have anti-inflammatory properties, which could decrease the risk of multiple diseases. In this large-scale prospective cohort study of nearly half a million UK adults, we evaluated the association between regular glucosamine supplement use and mortality from all causes, cardiovascular disease (CVD), cancer, respiratory disease, and digestive disease.

At baseline, 19.1% of the participants reported regular use of glucosamine supplements. During a median follow-up of 8.9 years, 19,882 all-cause deaths were recorded, including 3,802 CVD deaths, 8,090 cancer deaths, 3,380 respiratory disease deaths and 1,061 digestive disease deaths. The hazard ratios associated with glucosamine use were 0.85 for all-cause mortality, 0.82 for CVD mortality, 0.94 for cancer mortality, 0.73 for respiratory mortality and 0.74 for digestive mortality. The inverse associations of glucosamine use with all-cause mortality seemed to be somewhat stronger among current than non-current smokers.

Glucosamine and chondroitin supplements are often taken together in a single daily supplements, and it is therefore possible that our observed associations are driven by either of these supplements. To address this issue, we performed sensitivity analyses examining the associations of glucosamine use alone (excluding participants who took chondroitin) with all-cause and cause-specific mortality. We found that the estimates did not change substantially. Therefore, it is likely that glucosamine use may reduce the risk of mortality, regardless of the co-administration of chondroitin.

Several potential mechanisms could explain the inverse association between glucosamine use and mortality. First, nuclear factor-κB (NF-κB) has been implicated in several diseases, such as inflammation-related CVD and cancers. Glucosamine use may affect inflammation by inhibiting the transcription factor NF-κB from translocating to the nucleus, reducing inflammation and thus lowering related mortality. Aside from reducing inflammation, an animal study reported that glucosamine use could trigger a mimic response of a low carbohydrate diet, via reducing glycolysis and increasing amino acid catabolism in mice. This could explain the linkage between glucosamine use and its protective effect, as population-based studies found that low carbohydrate diets are indeed related to a reduced risk of mortality.

Naked mole-rats (NMRs) are the longest-lived rodents, showing minimal aging phenotypes. An unsolved paradox is that NMRs exhibit low intracellular anti-oxidant defence despite minimal aging. Here, we explained a link between these "contradicting" features by a phenomenon termed "senescent cell death" - senescence induced cell death in NMR cells due to their inherent vulnerability to reactive oxygen species and unique metabolic system.

Generally, the "free radical theory of aging", later modified to "mitochondrial free radical theory", is the well-known theory of aging mechanism. Intracellular reactive oxygen species (ROS), deriving especially from mitochondria, damages macromolecules such as lipids, DNA, and proteins, and the accumulated damages in tissues are assumed to contribute aging process. Indeed, the mitochondrial ROS production rate is negatively correlated with the maximal lifespan of animal species.

However, previous insights on responses of long-lived NMRs to ROS are puzzling: 1) Several reports suggested that NMRs have stronger anti-oxidant mechanisms. 2) However, many other reports suggested that NMRs exhibit low anti-oxidant defence. From young ages, NMR suffers greater oxidative damages in tissue DNA, protein, and lipids than mice. Nevertheless, the level of oxidative damage does not increase further and remains constant for more than 20 years. Thus, at least in part, NMR exhibits low intracellular anti-oxidant defence despite their delayed aging. These complex but interesting observations raise a possibility that NMR may have developed a unique system to remove damaged cellular components or the cells that suffered the oxidative damage during aging.

In mammalian cells, one of the typical "damaged" cellular status along with elevated oxidative damage is cellular senescence. Cellular senescence is an irreversible cell proliferation arrest induced in response to stresses such as DNA damage, oncogene activation, and telomere shortening. Cellular senescence contributes to avoidance of cancer formation by stopping proliferation of damaged cells. In addition, cellular senescence has important roles in tissue homeostasis, embryonic development, and wound healing. On the other hand, accumulation of senescent cells promotes age-related physiological deterioration and disorders, by secreting a bioactive "secretome" called senescence-associated secretory phenotype (SASP).

In NMR skin, we observed few senescent cells during aging or after ultraviolet irradiation, suggesting suppression of senescent cell accumulation in NMR tissue. We discovered that senescent NMR fibroblasts induce senescent cell death through retinoblastoma protein activation accompanied by autophagy dysregulation, increased oxidative damage, and accelerated H2O2-releasing metabolic pathways.

A recent study involved 2,675 people with an average age of 50 who did not have dementia. Researchers measured their cardiovascular risk factors at the start of the study: 43% were considered obese, 31% had high blood pressure, 15% were smokers, 11% had diabetes, and 9% had high cholesterol. Participants were given thinking and memory tests at the beginning of the study and five years later. Then researchers estimated the association of the five cardiovascular risk factors with decline in their performance on the thinking and memory tests that was not defined as dementia, but was faster than what was seen in a group of adults of similar ages.

Five percent of the participants had accelerated cognitive decline over five years. A total of 7.5% of those with high blood pressure had faster decline, compared to 4.3% of those who did not have high blood pressure. And 10.3% of those with diabetes had faster decline, compared to 4.7% of those who did not have diabetes. A total of 7.7% of current smokers had faster decline, compared to 4.3% of those who never smoked.

After adjusting for age, race, education, and other factors that could affect the risk of cognitive decline, researchers found that people who smoked were 65% more likely to have accelerated cognitive decline, those with high blood pressure were 87% more likely and those with diabetes had a nearly three times as likely to have accelerated cognitive decline. People who had one or two of the risk factors were nearly twice as likely to have accelerated decline than people with no risk factors. People with three or more of the risk factors were nearly three times as likely to have faster decline than those with no risk factors.

The global increase in food security due to modern long-term food storage coupled with the increase in worldwide global food transportation, and international marketing has reduced the cost of food, increasing its availability in the developed world. However, food commercialization and the shift toward production of processed and ultra-processed foods have revealed clear adverse effects, such as the identification of processed food as a major cause for over-eating and the increase in the risk of metabolic syndrome, obesity, and diabetes. As the brain is one of the primary energy-demanding organs in the human body, it comes with no surprise that the brain is highly affected by such metabolic disorders.

Worldwide, the life expectancy of males rose from 59.6 years in the 1980's to 69.0 years in 2015, whereas the life expectancy of females increased from 63.7 to 74.8 years, respectively. This increase in lifespan is correlated with multiple age-dependent pathologies which have also increased in prevalence, such as neurodegenerative disorders. It is plausible to argue that the combined effect of the continued increase in lifespan and life-long continuous food consumption leads to a dramatic increase in the prevalence of neurodegenerative disorders in the elderly population.

Studies in laboratory animals show that caloric restriction (decreased food intake or intermittent fasting) can extend lifespan in rodents and primates and delay the onset of age-related diseases such as hypertension and diabetes. Moreover, caloric restriction may protect neurons from degeneration and enhance adult neurogenesis and neuronal plasticity, which may protect the brain from a cognitive decline during aging and neurodegenerative diseases. One of the crucial processes that are adversely affected during aging is cellular autophagy, which is tasked with eliminating aggregated proteins, unhealthy organelles, and multiple intracellular components. Multiple mechanisms can explain the roles of fasting and caloric restriction in ameliorating neurodegeneration. One of the most studied mechanisms is the upregulation of autophagy via inhibiting mTOR activity.

The sobering statistics of one in three elderly people suffering from a type of age-related dementia call to devise a multi-pronged approach to targeting age-related neurodegenerative diseases. Synthesis of the current data indicates that not only age but also dietary lifestyles that changed dramatically during the twentieth century are at play. Many factors that are at play during aging have a role in promoting neurodegeneration, such as oxidative stress, accumulation of DNA damage, cell senescence, neuroinflammation, and decreased autophagic flux. Aging is also characterized by elevated levels of neuroinflammation that are transcriptionally regulated. Autophagy, however, is a cellular pathway that throughout life is predominantly regulated extrinsically in a nutrient-consumption mediated manner. This places food consumption as a major factor, along with aging itself, in promoting neurodegenerative disorders.

The aged population is currently at its highest level in human history and is expected to increase further in the coming years. In humans, aging is accompanied by impaired angiogenesis, diminished blood flow, and altered metabolism, among others. A cellular mechanism that impinges upon these manifestations of aging can be a suitable target for therapeutic intervention. Here we identify cell surface receptor CD47 as a novel age-sensitive driver of vascular and metabolic dysfunction. With the natural aging process, CD47 and its ligand thrombospondin-1 were increased, concurrent with a reduction of self-renewal transcription factors OCT4, SOX2, KLF4, and cMYC in arteries from aged wild-type mice and older human subjects compared to younger controls.

These perturbations were prevented in arteries from aged CD47 knockout mice. Arterial endothelial cells isolated from aged wild-type mice displayed cellular exhaustion with decreased proliferation, migration, and tube formation compared to cells from aged CD47 knockout mice. CD47 suppressed ex vivo sprouting, in vivo angiogenesis and skeletal muscle blood flow in aged wild-type mice. Treatment of arteries from older humans with a CD47 blocking antibody mitigated the age-related deterioration in angiogenesis. Finally, aged CD47 knockout mice were resistant to age- and diet-associated weight gain, glucose intolerance, and insulin desensitizationipedia.org/wiki/Insulin_resistance">insulin desensitization.

These results indicate that the CD47-mediated signaling maladapts during aging to broadly impair endothelial self-renewal, angiogenesis, perfusion, and glucose homeostasis. Our findings provide a strong rationale for therapeutically targeting CD47 to minimize these dysfunctions during aging.

The aim of the present study was to determine if the training status decreases inflammation, slows down senescence and preserves telomeres health in skeletal muscle in older compared to younger subjects, with a specific focus on satellite cells. Analyses were conducted on skeletal muscle and cultured satellite cells from vastus lateralis biopsies (n=34) of male volunteers divided into four groups: young sedentary (YS), young trained cyclists (YT), old sedentary (OS) and old trained cyclists (OT). The senescence state and inflammatory profile were evaluated by telomere dysfunction-induced foci (TIF) quantification, senescence associated b-gal (SA-b-Gal) staining and qRT-PCR.

Independently of the endurance training status, TIF levels (+35%) and the percentage of SA-b-Gal positive cells (+30%) were higher in cultured satellite cells of older compared to younger subjects. p16 (4-5 fold) and p21 (2-fold) mRNA levels in skeletal muscle were higher with age but unchanged by the training status. Aging induced higher CD68 mRNA levels in human skeletal muscle (+102%). Independently of age, both trained groups had lower IL-8 mRNA levels (-70%) and tended to have lower TNF-alpha mRNA levels (-40%) compared with the sedentary subjects.

All together, we found that the endurance training status did not slow down senescence in skeletal muscle and satellite cells in older compared to younger subjects despite reduced inflammation in skeletal muscle. These findings highlight that the link between senescence and inflammation can be disrupted in skeletal muscle.

Alzheimer's disease (AD) is the most common neurodegenerative disorder seen in age-dependent dementia. There is currently no effective treatment for AD, which may be attributed in part to lack of a clear underlying mechanism. Studies within the last few decades provide growing evidence for a central role of amyloid β (Aβ) and tau, as well as glial contributions to various molecular and cellular pathways in AD pathogenesis.

AD pathogenesis involves pathogenic contributions from multiple components and alterations in behavior of various cell types within the central nervous system. Aβ is generated in neurons and then released to the extracellular space, where it can be degraded or cleared by microglia and astrocytes. Increased Aβ production or impaired Aβ degradation/clearance leads to Aβ accumulation. Tau is mainly expressed in neurons, and highly modulated through various post-translational modifications. Abnormal PTMs, liquid-liquid phase separation, and pathogenic tau seeds can cause tau aggregation and accumulation through different mechanisms. Tau pathology may be propagated during disease progression, and glial cells play an important role in the process of seeding and dispersion. Forms of Aβ aggregates, together with tau accumulation, can cause neuronal dysfunction and glial activation and the subsequent neuroinflammation; these events are regulated by various receptors expressed in neurons, microglia and astrocytes.

Genetic factors can cause or affect AD pathogenesis. Early-onset AD is mainly due to mutations in APP and PS1/PS2, which are involved in Aβ generation, while late-onset AD is largely associated with a group of genes enriched in glial cells, such as APOE and TREM2, which are important for Aβ clearance and glial function. Therefore, differential mechanisms may be involved in different forms of AD. In addition, other factors such as aging, metal ion, virus, and microbiota may also contribute to AD pathogenesis via various mechanisms. Mechanisms for late-onset AD are complex and subtypes of late-onset AD may exist. However, most of the available AD animal models carrying early-onset AD-associated mutations can only mimic early-onset AD. Development of animal models to recapitulate pathogenesis of late-onset AD may be beneficial to compare early and late stage forms of AD. This may uncover mechanisms specific to late-onset AD which represents over 90% of AD cases, and potentially provide new insights to therapeutic targets for treatment.