Aging is a complex, multifactorial process that leads to loss of function and is the primary risk factor for major human pathologies including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. Although there is still much debate in the scientific community, proposals have been made to classify aging as a disease in order to develop therapeutic strategies to prevent or delay the onset of age-related illnesses. Increasing frailty with age leads to an increased risk of many diseases. These diseases are commonly referred to as age-related. Many pathogens are more infectious and prevalent in the elderly, and may be referred to as gerophilic (from Greek, géros "old man" and philia, "love"). Some infections, including COVID-19, are not exclusively gerophilic, as younger people may also become infected. However, these individuals have mild symptoms or remain asymptomatic, while the elderly experience substantially more severe symptoms and lethality. The term gerolavic (from Greek, géros "old man", and epilavís, "harmful") may more appropriately describe infections that cause the most harm in the elderly.

Statistics from the COVID-19 pandemic indicate that COVID-19 is a gerolavic infection, one that disproportionately affects the elderly. According to Worldometers, an online resource aggregating data on COVID-19, of the 139,580 people infected worldwide as of March 13, 2020, 70,733 patients had recovered and 5,120 had died. Based on these data, the mortality rates (number of deaths/number of cases), or the probability of dying if infected by the virus, were determined to be 3.6% for individuals aged 60-69, 8% for individuals aged 70-79, and 14.8% for patients aged 80 years or older. The majority of the infected population are 50 and older, while the majority of fatalities are 60 and older.

An open coronavirus analysis project provides further insight into the mortality rates of COVID-19, specifically using data from the Diamond Princess Cruise, where all passengers were exposed to SARS-CoV-2 for an extended period. Of the approximately 1,690 passengers over 65 years of age, 7 passengers died, suggesting a death rate of 0.41%. This death rate is approximately 4.3 times higher than that of influenza. As more countries start reporting statistics, these death rates are likely to be adjusted. These statistics indicate that the infectivity of SARS-CoV-2, and the severity and lethality of COVID-19, are age-related.

One of the possible causes of the age-associated increases in COVID-19 infection rate, severity, and lethality is immunosenescence. Immunosenescence is a well-known age-related process contributing to the global burden of disease. Among the factors contributing to immunosenescence is the chronic involution of the thymus with increased age. Indeed, the infection rates of COVID-19, separated by age, are correlated with involution of the thymus. The thymus gland is most active early in life, reaching maximum size within the first year. Its activity then declines with age until an individual reaches 40 to 50, after which there are negligible traces of the thymus remaining, replaced by fibrotic tissue. As a result of thymic involution, the number of naïve T cells exiting the thymus decreases significantly, with substantial declines in older age.

Age-associated immunosenescence leads to a reduced ability to resist infection, while infection produces biological damage and loss of homeostasis. This ultimately contributes to accelerated aging and the development of age-related diseases, and further accelerates immunosenescence. In support of this model, infections and other age-related diseases are among the main causes of death in the developed world and in developing countries.

Due to the gerolavic nature of COVID-19, the classical preventative measures and treatment strategies used for targeting infectious diseases may not be as effective, and there is a need for alternative geroprotective and senoremediative strategies. Here we compare the expected benefit of treatments for elderly populations (60 years and older) that are currently in development, including standard preventative strategies such as vaccines and antivirals targeting SARS-CoV-2, and the potential added benefit of speculative geroprotective strategies such as rapalogs, NAD+ boosters, senolytics, and stem cell treatment. These additional measures may be used in isolation or as adjuvant therapies to reduce infection risk, symptom severity, or improve vaccine efficacy.

Therefore, interventions that enable immunocompromised elderly to mount an immune response to newly developed vaccines are necessary to help eradicate the disease and reduce the associated mortality. To avoid substantial loss of life and quality of life, primarily among the elderly and vulnerable populations, governments and healthcare systems should investigate preventative and intervention strategies stemming from recent advances in aging research. As discussed in this paper, small clinical studies have shown that several geroprotective and senoremediative interventions, such as treatment with sirolimus and rapalogs, can induce immunopotentiation, increase resistance to infection, and reduce disease severity in the elderly, without severe side effects.

Many of these predicted geroprotectors are available as supplements; however, no meta-analysis or metaclinical trials have been performed at scale to evaluate their effectiveness. The COVID-19 pandemic highlights the paucity of clinical trials on the effects of dietary supplements and drugs on aging and immunosenescence. The existence of pseudoscience and anecdotal promotion in the supplement industry does not mean that protective compounds do not exist. Dietary supplement vendors and pharmaceutical companies need to actively engage in preclinical and clinical research to evaluate the effectiveness of the currently available products on immunosenescence and aging.

Previous studies on osteoporosis overwhelmingly focused on the etiology within bone tissue that locally induces the disease. In this study, we showed that osteoporosis is highly associated with reduction in hematopoietic autophagy activity in humans. We showed that an autophagy defect in the hematological system leads to severe bone loss. The disturbed osteocyte homeostasis is apparently caused by impaired type H blood vessels and possibly an aberrant alteration in the extracellular matrix (ECM) pathways that govern osteocyte homeostasis in hematopoietic autophagy-defective mice. Our results thus suggest that autophagy in the adjacent hematopoietic cells is essential to maintain bone homeostasis, and chronic hematopoietic autophagy deficiency can result in the development of osteoporosis in both mice and humans

While the osteal impact on hematopoiesis, in particular on the formation of bone marrow hematopoietic stem cell niches, is well documented, studies of hematopoietic regulation of osteocyte function have been inadequate. Hematopoietic regulation of osteoblast proliferation and differentiation was previously discussed largely with skepticism speculation. However, a recent study showed that loss of the hematopoietic stem cell factor GATA2 in the osteogenic lineage impairs trabecularization and mechanical strength of bone. Our present study of RNA sequencing revealed that impairment of hematopoietic cells by autophagy defect also led to enhanced iron activity, which may eventually lead to iron overload, a major cause of osteoporosis.

Hematopoietic cells and osteocytes are adjacent in the bone marrow niche environment. Normal hematopoiesis and bone homeostasis are interdependent. Men with low bone mineral density (BMD) or greater BMD loss have decreased circulating erythrocytes and lymphocytes and increased myeloid cells, and anemia or low blood cell counts are associated with declining BMD or increased fracture risk in the aged population. On the other hand, chronic disorders affecting hematopoiesis, such as sickle cell anemia and thalassemia, demonstrate clear skeletal phenotypes, including bone loss and increased fracture risk.

Bone marrow HSCs have been found to be capable of differentiating to osteoblasts through a mesenchymal intermediate. These findings suggest that the developmental capacity of HSCs is not restricted to hematopoietic lineages, but extends to osteogenic differentiation, possibly via the HSC potential to transdifferentiate to osteocytes. HSCs do not rest passively in their niche, but instead directly participate in bone formation and niche activities. Therefore, HSC functions and bone turnover are coupled in osteoporosis.

Finally, screening for expression of selected genes and an immunohistological assay identifies severe impairments in H vessels in the bone tissue, which results in disconnection of osteocytes from hematopoietic cells in the autophagy-defective mice. We therefore propose that hematopoietic autophagy is required for the integrity of H vessels that bridge blood and bone cells and that its deterioration leads to osteoporosis.

According to the free radical theory of aging, reactive oxygen species (ROS) have been proposed to be a major cause of aging for a long time. Meanwhile, it became clear that ROS have diverse functions in a healthy organism. They act as second messengers, and as transient inhibitors of phosphatases and others. In fact, their detrimental role is highly dependent on the context of their production. NADPH oxidases (Nox) have been discovered as a controllable source of ROS. NoxO1 enables constitutive ROS formation by Nox1 by acting as a constitutively active cytosolic subunit of the complex. We previously found that both Nox1 and NoxO1 were highly expressed in the colon, and that NoxO1-/- deficiency reduces colon health. We hypothesized that a healthy colon potentially contributes to longevity and NoxO1 deficiency would reduce lifetime, at least in mouse.

In contrast, here we provide evidence that the knockout of NoxO1 results in an elongated life expectancy of mice. No better endothelial function, nor an improved expression of genes related to longevity, such as Sirt1, were found, and therefore may not serve as an explanation for a longer life in NoxO1 deficiency. Rather minor systemic differences, such as lower body weight occur. One effect of low body weight might be the expression and activity of Sirt1 and PGC1α, which are upregulated in response to caloric restriction. However, neither Sirt1 nor PGC1α was upregulated in NoxO1 deficient organs. Accordingly, the Sirt1 downstream target eNOS was not differentially activated in NoxO1-/- mice. We conclude that Sirt1 is not the preliminary effector to prolong the lifespan of NoxO1-/- mice, when compared to wildtypes. Although not significantly different from wildtype mice, low body weight in NoxO1 mice may have other beneficial effects.

As a potential reason for longer life, we suggest better DNA repair capacity in NoxO1 deficient mice. Although final fatal DNA damage appears similar between wildtype and NoxO1 knockout animals, we identified less intermediate DNA damage in colon cells of NoxO1-/- mice, while the number of cells with intact DNA is elevated in NoxO1-/- colons. We conclude that NoxO1 deficiency prolongs lifetime of mice, which correlates with less intermediate and potentially fixable DNA damage at least in colon cells.

Recent research has identified targetable vulnerabilities of senescent cells that can be exploited by a novel group of drugs called senolytics. These compounds preferentially kill senescent cells by different mechanisms. Senolytics include the BCL-2 family inhibitors Navitoclax (ABT-263) and ABT-737; the flavonoid fisetin; combinations of tyrosine kinase inhibitors and flavonoids (e.g. dasatinib and quercetin); FOXO4-p53 interfering peptides; HSP90 chaperone inhibitors; and other compounds such as piperlongumine and cardiac glycosides. Senolytics have emerged as promising agents for treatment of pulmonary fibrosis, atherosclerosis, osteoarthritis, type 1 diabetes mellitus, type 2 diabetes mellitus, and neurocognitive decline. They can also rejuvenate aged hematopoietic stem cells and muscle stem cells and extend the lifespan of naturally aged mice.

Despite successful preclinical proofs-of-concept for senolytics, their potential translatability is hampered by their associated toxicities, necessitating the development of more specific, and less toxic, second-generation senolytics. Navitoclax has been validated in a variety of preclinical models showing high potency in killing senescent cells - however, it also has significant on-target haematological toxicity, including thrombocytopenia.

One consistent feature of senescent cells is their enrichment in lysosomes and lysosomal proteins, including senescence-associated β-galactosidase (SA-β-gal) which is widely used as a marker of senescence. We previously showed that the encapsulation of nanoparticles with galacto-oligosaccharides (GalNPs) is an efficient method to preferentially deliver cytotoxic drugs and tracers to the lysosomes of senescent cells where SA-β-gal activity digests the galacto-oligosaccharides, thereby releasing the cargo. We have also shown that a fluorescent probe covalently linked to multi-acetylated galactose is preferentially digested by senescent cells, releasing the free fluorophore.

Here, we have modified Navitoclax with an acetylated galactose to exploit the enriched SA-β-gal activity of senescent cells. Using a variety of model systems, we show that galacto-conjugation of Navitoclax, which we name Nav-Gal, results in a prodrug with selective, pro-apoptotic senolytic activity released in senescent cells that is dependent on GLB1 activity. Galacto-conjugation of Navitoclax reduces thrombocytopenia in treated mice at therapeutically effective doses, as well as apoptosis of platelets in human blood samples treated ex vivo. Overall, we propose galacto-conjugation of cytotoxic drugs as a versatile methodology for developing second-generation prodrugs with high senolytic activity and reduced toxicity. We provide evidence of the efficacy of combining senescence-inducing chemotherapies with senotherapies in cancer, with potential for clinical application.

As the central protease of the ubiquitin-proteasome pathway, the proteasome has long been considered an attractive target for drugs potentially affecting multiple aspects of cell physiology. Indeed, small molecules targeting the proteasome have entered the clinic with great success. However, their scope at present is very limited: all proteasome-modifying compounds currently approved or clinically tested as drugs are competitive inhibitors and all are used to treat advanced blood cancers. Here we turn to the opposite side of pharmacological intervention into the proteasome: augmentation of catalytic activity. Since dysfunction of proteasome-mediated controlled protein degradation is a hallmark of both cellular aging and neurodegenerative diseases, enhancement of the enzyme's activity should be considered an attractive therapeutic option.

The complex structure of the catalytic core 20S proteasome (the "core particle") presents fascinating options for allostery-based augmentation. The peptidase responsible for post-hydrophobic (chymotrypsin-like, ChT-L) cleavages is considered a rate-limiting "workhorse" and is the major target for inhibitors and activators alike. Indeed, overexpression of a catalytic subunit harboring the active site of the ChT-L peptidase has been shown not only to extend lifespan but also to reduce age-related cognitive decline in animal models. However, reports on pharmacological augmentation are limited to in vitro and cell culture studies.

Here, we describe a series of short, modified peptides based on the basic domain of the viral Human Immunodeficiency Virus-1 (HIV-1) Tat protein. Among many intracellular effects, the HIV-1 Tat protein inhibits the core proteasome. In our previous studies, we noted that short peptide fragments of HIV-1 Tat displayed peculiar in vitro properties: they inhibited detergent-treated core particle but mildly activated the latent core. However, treatment with detergent, although convenient for in vitro assays, yields mildly denatured proteasome and, under these far-from-physiological conditions, likely with destroyed natural allosteric routes.

Therefore, we turned our attention to the activating properties of HIV-1 Tat protein-derived "TAT peptides". After observing a strong in vitro proteasome augmentation by modified HIV-1 Tat-derived peptides, we tested selected compounds in cell culture. In a separate study, we found that proteasome stimulation by TAT peptides partially prevented the cognitive deficits and mortality in animal models of Alzheimer's disease. The very encouraging results included increased proteasome-mediated turnover of amyloid precursor protein (APP) and β-secretase (which cleaves APP to generate β-amyloid peptide), concomitant with lowered levels of β-amyloid, lowered mortality and protection against cognitive decline. We propose that the proteasome-stimulating TAT pharmacophore provides an attractive lead for future clinical use.

From this large, retrospective cohort study targeting 3546 Japanese Olympic athletes, we observed significant lower mortality among Olympians compared with the Japanese general population. The overall standardised mortality ratio (SMR) was 0.29. The results were consistent with previous studies conducted in other non-Asian countries, but the SMR was lower than in previous studies. A retrospective cohort study targeting 203 French Olympic rowers reported that the SMR for all causes of death was 0.58. Another retrospective cohort study targeting 2403 French Olympic athletes reported a SMR of 0.49 among women and 0.51 among men. A third retrospective cohort study of 233 Croatian male Olympic medalists reported a SMR of 0.73.

In the analysis by total number of participation in the Olympic Games, significantly higher mortality was observed among those who participated in the Olympics more than twice compared with those who participated only once. The underlying reason for this may be that those who participated in Olympic Games many times may have had long careers as elite athletes. To be continuously successful, they could have been exposed to exercises with high intensity for long periods, which may have led to higher mortality compared with those who participated only once.

We conducted cohort classification by sport discipline according to the nine combinations of static and dynamic intensity of sports disciplines, and demonstrated the association between intensity of sports disciplines and mortality. We did not observe significantly higher mortality among athletes who participated in disciplines of highest static and highest dynamic intensity. This could be explained in part by their exercise habits after retiring from international competitions. Although a study reported that those capable of prolonged vigorous physical exercises lived longer compared with the general population, Olympic athletes involved in sports disciplines with high intensity may not necessarily continue sports activities after retirement. The habit of sports activities after retiring from athletics may have more influence on mortality than the static/dynamic intensity of each sports discipline.

Physiological aging is a complex process, influenced by a plethora of genetic and environmental factors. While being far from fully understood, a number of common aging hallmarks have been elucidated in recent years. Among these, transcriptomic alterations are hypothesized to represent a crucial early manifestation of aging. Accordingly, several transcription factors (TFs) have previously been identified as important modulators of lifespan in evolutionarily distant model organisms.

Based on a set of TFs conserved between nematodes, zebrafish, mice, and humans, we here perform a RNA interference screen in C. elegans to discover evolutionarily conserved TFs impacting aging. We identify a basic helix-loop-helix TF, named HLH-2 in nematodes (Tcf3/E2A in mammals), to exert a pronounced lifespan-extending effect in C. elegans upon impairment. We further show that its impairment impacts cellular energy metabolism, increases parameters of healthy aging, and extends nematode lifespan in a reactive oxygen species dependent manner.

We then identify arginine kinases, orthologues of mammalian creatine kinases, as a target of HLH-2 transcriptional regulation, serving to mediate the healthspan-promoting effects observed upon impairment of hlh-2 expression. Consistently, HLH-2 is shown to epistatically interact with core components of known lifespan-regulating pathways, i.e. AAK-2/AMPK and LET-363/mTOR, as well as the aging-related TFs SKN-1/Nrf2 and HSF-1. Lastly, single-nucelotide polymorphisms (SNPs) in Tcf3/E2A are associated with exceptional longevity in humans. Together, these findings demonstrate that HLH-2 regulates energy metabolism via arginine kinases and thereby affects the aging phenotype dependent on ROS-signaling and established canonical effectors.

Overuse-induced musculoskeletal disorders are widely understood to be injuries and disorders affecting the musculoskeletal system. Tissue fibrosis is a pathological hallmark of overuse-induced muscle injuries and is considered to play key roles in associated motor dysfunction. Such fibrosis is thought to distort dynamic properties of tissue and contribute to functional declines due to adherence of adjacent structures. We have shown that inflammation is a key driver of further fibrosis, and that early use of anti-inflammatory drugs, ergonomic task reduction and manual therapy treatments are able to prevent their development. However, treatments aimed at reducing established muscle and other tissue fibrosis have proved to be more difficult, because once deposited and cross-linked, the extracellular matrix becomes resistant to degradation.

Blocking CCN2 signaling has shown promise for many fibrotic disorders. Downregulation of CCN2 reduces liver fibrosis and limits hypertrophic scarring without affecting wound healing. We recently found that CCN2 is critical to the early progression of chronic overuse-induced muscle fibrosis and grip strength declines in rats that performed an operant reaching, grasping, and lever-pulling task at high repetition high force (HRHF) levels for three weeks. CCN2 inhibition reduced this early progression of fibrosis and improved motor declines. However, continued performance of the HRHF task for 18 weeks, untreated, induces even greater muscle fibrosis and motor declines than at earlier weeks. Therefore, we examined for the first time whether inhibition of CCN2 using this antibody is able to reduce established skeletal muscle fibrosis in our operant rat model of overuse injury.

We show here that 6 weeks of rest combined with systemic inhibition of CCN2 significantly reduced established skeletal muscle fibrosis and improved motor function, compared to control rat levels. We again show that increased muscle fibrosis was mirrored by increased serum levels of CCN2, adding further support to its use as a serum biomarker of underlying tissue fibrosis occurring with overuse injuries as well as other diseases associated with enhanced fibrogenic activity.

Human mesenchymal stem cells (hMSCs) have been considered as one of the most promising cell sources for cell-based cardiac regeneration therapy because of their proven safety and notable paracrine effects to secrete numerous antiapoptotic and angiogenic growth factors, which enabled them to be a more competitive agent for clinical applications. However, unlike promising results obtained from preclinical models of myocardial infarction (MI), recent multiple meta-analyses have debated whether the therapeutic potential of hMSC treatment is sufficient. While these clinical trials successfully demonstrated the feasibility and safety of hMSC treatment, the researchers were unable to show significant functional benefit.

In response, diverse approaches have been attempted to enhance the therapeutic efficacy of hMSCs in treating MI. For instance, genetically engineered hMSCs overexpressing a number of antiapoptotic proteins, growth factors, or prosurvival genes - such as vascular endothelial growth factor (VEGF), insulin-like growth factor 1 (IGF-1), and hepatocyte growth factor (HGF) - showed increased survival and retention in vivo resulting in improved cardiac function and myocardial angiogenesis in MI-induced hearts. However, these approaches require genetic modification and, therefore, are incompatible with clinical applications.

Another strategy to bolster the therapeutic potential of hMSCs is priming/preconditioning the hMSCs - which exposes them to physical treatments (e.g., hypoxia and heat shock), pharmacological agents, growth factors, distinct types of biomaterials, modified culture conditions, or other various molecules, including microRNAs - in vitro before transplantation into the hearts. However, it appears that the priming application only provides a short-term benefit.

Consequently, for hMSCs to be used more effectively for comprehensive cardiac repair, an innovative method that can maintain the priming effect of hMSCs more consistently and effectively must be developed. In the present study, we sought to develop a strategy, namely, in vivo priming, which could prime hMSCs in intact hearts in vivo. To induce and maintain the beneficial effects of priming persistently in situ, we loaded MSCs isolated from human bone marrow (BM-MSCs) together with genetically engineered HGF-MSCs (HGF-eMSCs) that continuously secrete HGF within a three-dimensional (3D) cardiac patch, which was implanted in the epicardium of MI-induced hearts. Subsequently, we demonstrated that the primed BM-MSCs had a higher survival rate compared with unprimed BM-MSCs in the patches while they were attached to the MI hearts, which led to a significant improvement in cardiac function and an enhancement of vessel formation after MI.

A hallmark of many neurodegenerative diseases is the progressive formation of insoluble protein aggregates. There are two main factors that cause protein aggregation in neurodegenerative diseases: mutations in genes encoding aggregate-prone proteins and the decline of cellular degradation functions, in particular of the autophagy-lysosomal pathway (ALP).

ALP is a major process for degrading intracellular macromolecules and generating energy or building blocks to make other macromolecules. ALP relies on the engulfment of cargos to be degraded (macromolecules or damaged organelles) in double-membrane vesicles (autophagosomes), which, therefore, fuse with endosomes/lysosomes to form autolysosomes, where autophagosome contents are degraded by lysosomal enzymes. ALP plays a key role in protein homeostasis and in the clearance of protein aggregates (processes that are particularly important in non-dividing neurons).

Mounting evidence also shows that protein aggregation itself may affect ALP, thus generating a vicious cycle, which boost protein aggregation and toxicity. Different works have shown that the aggregated forms of α-synuclein can bind the lysosome, thus impairing the chaperone-mediated autophagy or inducing lysosomal rupture. The interplay between protein aggregation and ALP dysfunction is crucial in driving neurodegenerative processes in a number of neurological conditions.

Changes in cognitive performances and cardiovascular disorders represent a normal phenomenon of the aging process. Cardiovascular risk factors, such as smoking, obesity, diabetes mellitus, increased cholesterol, and systemic blood pressure (BP) levels, and an inadequate lifestyle may compromise also cerebral blood flow, which in turn can negatively affect cognitive performance. Moreover, the same age-related anatomical and functional cardiac changes, including also the autonomic nervous system (ANS), determine cardiac output alteration, causing cerebral blood flow modulation. This variation could interfere with microcirculation and cause cerebral ischemia, particularly in those brain sites that control the different cognitive domains.

Evidence supports the relevance of ANS study by heart rate variability (HRV) assessment as a tool for the noninvasive analysis of cardiovascular autonomic function. HRV, defined as a marker identifying the balance between sympathetic and parasympathetic tone, predicts total mortality, sudden death, cardiovascular disease risk, as well as other morbidities. It represents the measure of physiological variation in the interval between consecutive heart sinus beat or in the fluctuations between instantaneous heart rates and provides the importance that the ANS has regarding cardiovascular health and prognosis.

We assessed the relationship between long-term heart rate variability (HRV), as a measure of autonomic nervous system (ANS) functioning, and cognitive performance in elderly patients representative of outpatients in a real-life setting. 117 patients underwent anthropometric evaluation, cardiac assessment by 12-lead electrocardiogram, 24-hour electrocardiogram recording, and blood pressure (BP) measurement, as well as global cognitive evaluation. Our results show that an increased sympathetic activity, but not decreased vagal activity, is associated with better cognitive performances. These results support the sympathetic autonomic function, in that the relationship between better cognitive performances and a moderate prevalence of autonomic function appears dependent on long-term changes in heart rate, mediated by sympathetic activation.

Exercise provides many health benefits, including weight loss, improved lipid profiles, and improved insulin sensitivity. It is particularly relevant in the era of high-prevalence childhood and adult obesity and cardiometabolic disease. Exercise is a core tenet of all cardiovascular prevention guidelines, and degree of physical fitness is a strong predictor of cardiovascular mortality.

Metabolites are a diverse array of biochemicals that together capture an individual's metabolic state. They are particularly useful in the investigation of cardiometabolic diseases. Furthermore, they can characterize response to both acute and chronic exercise. Several studies have revealed key changes in lipolysis, glycolysis, glycogenolysis, citric acid cycle, and amino acid metabolism after a single/acute aerobic exercise session and identified differences in metabolite substrate use between fit and unfit individuals. However, much less work has been done with respect to metabolic changes following chronic exercise training. These studies reported increases in microbiome-derived tryptophan metabolites and acylcarnitines, and decreases in adenine nucleotides.

We analysed changes in metabolomic profiles at the end of an 80-day exercise intervention compared to baseline, and the association of metabolite changes with changes in clinical parameters. Global metabolism was dramatically shifted after the exercise training programme. Fatty acids and ketone body substrates, key fuels used by exercising muscle, were dramatically decreased in plasma in response to increased aerobic fitness. There were highly significant changes across many classes of metabolic substrates including lipids, ketone bodies, arginine metabolites, endocannabinoids, nucleotides, markers of proteolysis, products of fatty acid oxidation, microbiome-derived metabolites, markers of redox stress, and substrates of coagulation.

For the first time, therefore, we were able to provide an accurate report of the degree of increased consumption of fatty acid and ketone body substrates by trained, energy-efficient muscle. We also captured heretofore unseen, in terms of scale and scope, shifts in metabolism across many different substrates. These findings have important implications in cardiovascular disease prevention and risk reduction regimes.

Dietary restriction (DR) is defined as a decrease in energy consumption without reducing nutritional value. This simple dietary intervention has been shown in a wide range of experimental animals to extend lifespan and decrease the incidence of several age-related diseases. The definition of DR has been expanded from an alternative description of caloric restriction (CR) to also encompass a broader scope of interventions, including short-term starvation, periodic fasting, fasting-mimetic diets, and intermittent fasting (IF).

IF has been proven to be advantageous to various organ systems in the body and acts as a mild metabolic stressor. It has been postulated that IF is able to cause powerful changes in the metabolic pathways in the brain via an increase in stress resistance, and breakdown of ketogenic amino acids and fatty acids. Experimental studies have also shown that IF is neuroprotective against acute brain injuries such as stroke, and neurodegenerative diseases. In addition, recent studies have also shown that IF can lead to an increase in neurogenesis levels in the hippocampus.

We evaluated the impact of 3 months of IF (12, 16, and 24 hr of food deprivation on a daily basis) on hippocampal neurogenesis in mice using immunoblot analysis. We investigated the expression levels of molecular and cellular components of the hippocampal region, focusing specifically on Notch activation and associated proteins that are known to promote hippocampal neurogenesis such as brain-derived neurotrophic factor (BDNF) and cAMP response element-binding protein (CREB).

Three-month IF significantly increased activation of the Notch signaling pathway, neurotrophic factor BDNF, and downstream cellular transcription factor, cAMP response element-binding protein (p-CREB). The expression of postsynaptic marker, PSD95, and neuronal stem cell marker, Nestin, was also increased in the hippocampus in response to 3-month IF. These findings suggest that IF may increase hippocampal neurogenesis involving the Notch 1 pathway.

Aging and Alzheimer's disease (AD) are both associated with diminished blood-brain barrier (BBB) integrity and an opening for T cell migration into the central nervous system (CNS). In the parenchyma, bidirectional crosstalk occurs between the infiltrating cells and the resident glial cells; activated microglia impair BBB function by releasing several inflammatory modulators and thus lead to hyperpermeability; and the resulting T cell infiltration, in turn, favors increased microglial activation by secreting proinflammatory cytokines or acting in a protective manner toward senescent microglia.

We performed RNA-seq analyses on microglia and astrocytes freshly isolated from wild-type and APP-PS1 (AD) mouse brains at five time points to elucidate their age-related gene-expression profiles. Our results showed that from 4 months onward, a set of age-related genes in microglia and astrocytes exhibited consistent upregulation or downregulation (termed "age-up"/"age-down" genes) relative to their expression at the young-adult stage (2 months). Most age-up genes were more highly expressed in AD mice at the same time points. Bioinformatic analyses revealed that the age-up genes in microglia were associated with the inflammatory response, whereas these genes in astrocytes included widely recognized AD risk genes, genes associated with synaptic transmission or elimination, and peptidase-inhibitor genes.

The results of this study indicate that microglia exhibit an increase in responsiveness to inflammation stimuli with age, which is reflected by the consistently elevated expression of inflammatory-response genes, whereas astrocytes appear to function as "preservers" of inflammation, which is reflected by the upregulation of peptidase-inhibitor genes upon aging.

Heart disease is the leading cause of death worldwide. The major cause of heart failure is the death of the myocardium caused by myocardial infarction, detrimental cardiac remodeling, and cardiac fibrosis occurring after the injury. This study aimed at discovering the role of the anti-aging protein α-klotho (KL), which is the co-receptor of fibroblast growth factor-23 (FGF23), in cardiac regeneration, fibrosis, and repair.

FGF23 is the most recently discovered fibroblast growth factor and functions as an endocrine hormone that regulates phosphate homeostasis through binding to FGFR and KL, its coreceptor in the kidney and parathyroid glands. Elevated levels of circulating FGF23 have been associated with left ventricular hypertrophy, and it has been suggested that FGF23 exerts a direct effect on the myocardium. Interestingly, the co-receptor of FGF23, KL, has been shown to exhibit renal protective functions independent of FGF23/FGFR signaling.

We found that the anti-apoptotic function of soluble KL in isoproterenol-treated cardiomyocytes was independent of FGF23 in vitro. In vivo, isoproterenol-induced cardiac fibrosis and cardiomyocyte and endothelial cell apoptosis were reduced by KL treatment. Moreover, the number of Ki67-positive endothelial cells and microvessel density within the isoproterenol-injured myocardium were increased upon KL treatment. However, by using genetic fate-mapping models, no evident cardiomyocyte proliferation within the injured myocardium was detected with or without KL treatment. Collectively, the cardioprotective functions of KL could be predominantly attributed to its anti-apoptotic and pro-survival activities on endothelial cells and cardiomyocytes. KL could be a potential cardioprotective therapeutic agent with anti-apoptotic and pro-survival activities on cardiomyocytes and endothelial cells.