Different species have very different lifespans ranging from less than 1 day for mayflies to more than 400 years for the Greenland shark. However, the exact cause of these differences in longevity are still largely unknown. Our group recently showed that the rate of telomere shortening with age correlates with lifespan in a variety of species from birds to mammals. Species with very fast telomere shortening rates such as mice have very short lifespans, and species with very slow telomere shortening rates such as humans have very long lifespans. It is interesting to note that species that share a similar longevity in spite of being evolutionarily distant like flamingos and elephants, also show a similar rate of telomere shortening, while evolutionarily closer species like mice and elephants, show very different longevities and also have very different rates of telomere shortening.

These findings suggest that longevity can be determined, at least in part, by epigenetic traits, such as the rate of telomere shortening. Furthermore, these findings pose the interesting question of which is the molecular determinant by which higher telomere shortening rates lead to shorter longevities. An obvious answer is that higher rates of telomere shortening will be associated to faster accumulation of critically short/dysfunctional telomeres, which are known to contribute to activation of a persistent DNA damage response stemming from telomeres, which leads to loss of cell viability and aging phenotypes. Thus, species that shorten telomeres at faster rates will reach telomere exhaustion and trigger a persistent DNA damage response earlier than those species that are able to maintain telomeres protected for a longer period of time. A short/dysfunctional telomere is recognized by the cell as an irreparable DNA double strand break (DSB), triggering a persistent DNA damage response which results in phosphorylation of γH2AX, and which eventually leads to cell death and/or senescence. In turn, induction of cellular senescence either owing to critically short telomeres or to other insults is also associated with increased γH2AX levels, involving in some instances the mTOR pathway. Thus, accumulation of cells with DNA damage throughout lifespan should also correlate with species longevity.

Here, we find that increased global rates of DNA damage, as determined by the DNA damage marker γH2AX which detects occurrence of double stranded DNA breaks in the genome, inversely correlates with species longevity. In particular, we determined here the rates of increase of the DNA damage marker γH2AX in leukocytes of phylogenetically distant species of birds and mammals in parallel and using the same experimental method. Previous studies have also shown a correlation between certain types of DNA damage and aging. Indeed, DNA damage accumulation with aging and telomere shortening may be related processes. Critically short telomeres as the result of cell proliferation throughout life to repair damaged tissues trigger a DNA damage signal specifically at telomeres.

We also measured the percentage of short telomeres of the species in this study, and we found that all of the species showed an increase in the percentage of short telomeres with age. This result is concomitant with the fact that average telomere length shortens with age in many species. Several studies have suggested that the percentage of short telomeres is more indicative of health and senescence than average telomere length. The percentage of short telomeres is an important metric since it is the length of the shortest telomere in a cell that induces a DNA damage response and cell senescence rather than the average telomere length of the telomeres on all of the chromosomes. Here we also noticed a mild trend for species with longer maximum lifespans to have a lower rate of increase of percent short telomeres, thus accumulating short telomeres more slowly with age. We also observed that species with the highest rates of γH2AX increase have the highest rates of increase of percent short telomeres with age. These results make a connection between γH2AX DNA damage, short telomeres, and lifespan. As cells accumulate DNA damage and short telomeres, they will enter into a state of senescence, thus accelerating the aging process and shortening lifespan.

The functional state of the central nervous system (CNS) is greatly dependent on the quality of the vasculature. As the centuries old saying goes: "A man is as old as his arteries". Today, especially for the brain, this concept should be redefined: You are as old as your microvessels and capillaries. There is increasing evidence that the cerebral microvasculature and the neurovascular unit play a critical role in age-related brain dysfunctions. The multitude of brain microvascular changes accompanied by aging includes endothelial dysfunction, blood-brain barrier (BBB) breakdown, decrease in blood flow, microhemorrhages, vessel rarefication, and neurovascular uncoupling.

Cerebral endothelial cells (CECs) lining brain capillaries are considered the principal barrier forming endothelial cells. They are interconnected by a continuous line of tight junctions and characterized by a high number of mitochondria and low number of caveolae. These characteristics contribute to the formation of a paracellular and transcellular barrier.

With aging, the density of brain vasculature is decreased and cerebrovascular dysfunction appears to precede and accompany cognitive dysfunction and neurodegeneration. Cerebrovascular angiogenesis is decreased and cerebral blood flow is inhibited by anomalous blood vessels such as tortuous arterioles and thick collagen deposits in the walls of veins and venules. In most mammals, the capacity of CECs to divide is limited and endothelial cells are prone to be senescent. Aging is associated with endothelial dysfunction, arterial stiffening, and remodeling, impaired angiogenesis, defective vascular repair and with an increasing prevalence of atherosclerosis. In the aging brain cerebral blood flow declines and perfusion pressure either is constant or increases.

The paracellular barrier properties of CECs are determined by the tight junction (TJ), which are composed of transmembrane proteins that control the transport across the intercellular space between adjacent cells and cytoplasmic plaque. Limited data is available on what changes develop in the function of the BBB and the composition and structure of endothelial TJs in the healthy aging human brain. In a meta-analysis of BBB permeability studies, the barrier function was negatively impacted by age. Though there were some discrepancies, paracellular permeability was generally increased in the aged human brain. Permeability changes are likely the result of decreased expression and disorganized localization of TJ proteins.

With the building evidence that dysfunction of the microvasculature is not just coincident but is part of the underlying mechanisms of aging and associated neurovascular and neurological disorders, new therapeutic possibilities are opened. The significant heterogeneity of BBB disruption data in studies using aging postmortem brain tissue suggests that more data is necessary to clearly understand the role of BBB disruption and to see whether it is a symptom or a cause. Thus further comprehensive BBB TJ and permeability studies are needed in the field of aging and aging associated disorders.

We report that Werner syndrome (WS) is associated with a significant mitochondrial dysfunction, mainly manifested as defective mitophagy. This is reflected in lower NAD+ levels across species from worms to humans. NAD+ supplementation improves mitochondrial function and other age-related metabolic outcomes. Mitochondrial disease can manifest itself in multiple clinical outcomes amongst which neurodegeneration and impaired metabolism are common. Some features of WS may be explained by genomic instability due to mutation in the gene encoding the Werner protein (WRN), an important DNA helicase/exonuclease involved in DNA repair, telomere and heterochromatin maintenance, and cancer regulation. However, the relationship between WRN mutations and the syndrome's severe dysregulation of energy metabolism is unclear.

Mitochondrial quality and function decline with age, contributing to insulin resistance and metabolic diseases in the elderly. Mitochondrial quality control is regulated by biogenesis and mitophagy. Mitophagy involves the targeting of damaged mitochondria to the lysosomes wherein the mitochondrial constituents are degraded and recycled. Defective mitophagy is prominent in aging and age-predisposed disorders, including metabolic diseases and neurodegeneration. However, the role of mitophagy in WS has not been investigated.

The metabolic molecule nicotinamide adenine dinucleotide (NAD+) is emerging as a fundamental regulator of mitochondrial homeostasis, genome stability, neuroprotection, healthy aging, and longevity. Interestingly, genetic and/or pharmacological upregulation of intracellular NAD+ levels protects against obesity and type 2 diabetes in rodents, and against age-related diseases and neurodegenerative diseases such as Alzheimer's disease.

We therefore examined whether mitochondrial dysfunction and NAD+ depletion occur in WS, and if so, how it contributes to the molecular pathology in WS. We report that NAD+ depletion is a major driver of the severe metabolic dysfunction in WS through dysregulation of mitochondrial homeostasis. At the organismal level, NAD+ repletion remarkably extends lifespan and delays accelerated aging, including stem cell dysfunction, in Caenorhabditis elegans and Drosophila melanogaster models of WS. Our findings suggest that accelerated aging in WS is mediated by impaired mitochondrial function and mitophagy, and that bolstering cellular NAD+ levels counteracts WS phenotypes.

Atrial fibrillation (AF) is the most common cardiac arrhythmia, and is associated with considerable morbidity and mortality. The prevalence of AF increases with increasing age and is related to the increasing prevalence of comorbidities and structural remodelling of the atria that is believed to occur with aging. Increasing atrial fibrosis is known to be associated with more frequent paroxysms of AF, persistent AF, and refractoriness to medical therapy.

Recently, a considerable proportion of elderly patients with heart failure with preserved ejection fraction (HFpEF) have been found to have isolated amyloid deposits in the heart. Further, a proportion of patients with valvular heart disease have been found to have clinically undetected amyloid deposits on atrial biopsies obtained during cardiac surgery and such deposits have been shown to be associated with an increased risk of AF. The role of such clinically undetected atrial amyloid deposits in the aetiopathogenesis of AF occurring in the absence of valvular heart disease has not been previously evaluated.

In this study, we sought to assess the prevalence of AF in patients with clinically undetected isolated cardiac amyloidosis (ICA) detected at autopsy and identify electrocardiographic (EKG) markers of such amyloid deposits. A total of 1083 patients were included in the study and 3.1% of patients were found to have asymptomatic ICA. Patients with ICA were older and had a higher odds of AF independent of age and CHA2DS2VASc score. Amongst patients with AF, those with ICA were more likely to have persistent forms of AF and had a lower sinus rhythm P-wave amplitude. Further studies are required to further define this entity, identify imaging modalities to aid in antemortem diagnosis of ICA and to establish the optimal management strategies in these patients.

Vascular dysfunction is a major complication in type 2 diabetes (T2D). It has been suggested dysregulation of autophagy is associated with various cardiovascular diseases. However, the relationship between autophagy and vascular dysfunction in T2D remains unclear. Thus, we examined whether reduced autophagy is involved in vascular dysfunction and stimulation of autophagy could improve vascular function in diabetes.

Ten to 12-week old male type 2 diabetic (db-/db-) mice and their control (db-/db+) mice were treated with rapamycin or trehalose. Mesenteric arteries (MAs) were mounted in the arteriography and diameter was measured. Western blot analysis and immunofluorescence staining were assessed. Myogenic response (MR) was significantly increased, whereas endothelium-dependent relaxation (EDR) was significantly attenuated in the MAs of diabetic mice. These results were associated with increased expressions of LC3II, p62, and beclin-1 in diabetic mice.

Treatment of autophagy stimulators significantly reduced the potentiation of MR and improved EDR in the diabetic mice. Furthermore, autophagy stimulation normalized expressions of LC3II, p62, and beclin-1 in the diabetic mice. In addition, phosphorylation level of eNOS was decreased in diabetic mice, which was restored by rapamycin and trehalose. In conclusion, T2D impairs vascular function by dysregulated autophagy. Therefore, autophagy could be a potential target for overcoming diabetic microvascular complications.

In the last two decades, the perception of skeletal muscle as a pure locomotors unit has shifted. Muscle is increasingly recognized as an organ with immune regulatory properties. As such, skeletal muscle cells modulate immune function by signalling through different soluble factors, cell surface molecules, or cell-to-cell interactions. Although our knowledge of the muscle-immune system interplay has advanced considerably, the impact of age is relatively unknown. Sarcopenia may severely disturb this interaction, providing a potential explanation for the observed clinical outcomes of sarcopenic patients

Muscle is increasingly recognized as an endocrine organ producing and releasing cytokines and other peptides, which exert autocrine, paracrine, and endocrine activity on numerous tissues. Consequently, these soluble factors are commonly termed myokines. Proteomic profiling has been applied to the secretome of skeletal muscle and identified more than 300 potential myokines. Myokines such as IL-6, IL-7, IL-15, or LIF have been shown to modulate the immune system. Remarkably, serum concentrations of myokines such as IL-7 and IL-15 are inversely correlated with age, suggesting a link between skeletal muscle and age-dependent loss of immune system function.

As humans age, the immune system undergoes drastic changes. The umbrella term immune senescence is used to encompass these changes. Moreover, ageing is associated with increased serum levels of pro-inflammatory molecules. Skeletal muscle exhibits immune regulatory properties and that chronic, low-grade inflammation may induce muscle wasting. The concept of skeletal muscle as a regulator of immune function is relatively new and adds a new layer of complexity to the muscle-immune system link. Consequently, the muscle-immune system connection might be bidirectional: chronic, low-grade inflammation induces muscle catabolism via pleiotropic mechanisms mediated by the inflammatory secretome. Concurrently, homeostasis of skeletal muscle is, in part, responsible for healthy immune function. However, when dysregulated, insufficient myokine signalling, alteration of membrane bound factors towards a pro-inflammatory profile and impaired regenerative capacities of immune cells might result in disruption of immune system function.

We propose that biological aging may disturb the equilibrium of muscle-immune system homeostasis with skeletal muscle acting as a potential central link between sarcopenia and immune senescence. Healthy muscle function is gradually lost in an aging biological system due to physical inactivity, metabolic changes and the accumulation of chronic, low-grade inflammation. In turn, impaired muscle function curtails skeletal muscle cell signalling needed for immune regulation and maintenance, culminating in a vicious cycle in which immune and muscle system dysfunction sustain each other.

The genetic propensity of certain species for longevity and anti-aging is a challenging problem in vertebrate biology. Of particular interest are the genes that influence life expectancy differences among species. These genes are expected to be the real longevity genes of interest and should explain the wide differences in the rate of aging among diverse species and why similarly sized rodents or primates sometimes have anomalous life expectancies - such as naked mole-rats or humans.

No such genes have been unequivocally identified. We performed a computer-aided analysis of data relevant to lifespan and made a bioinformatic search for the genes, the loss of which might modulate lifespan. This search is based on the general idea that such genes are lost in a predefined set of species but are present in another predefined set of species. Examples of such pairs of sets include long-lived vs short-lived, homeothermic vs poikilothermic, among others. Species are included in one of two sets depending on the property of interest, such as longevity or homeothermy. A bioinformatics method and software relevant to the idea are universal towards these sets and the property that defines them.

Here, the proposed method was applied to study the longevity of Euarchontoglires species. It largely predicted genes that are highly expressed in the testis, epididymis, uterus, mammary glands, and the vomeronasal and other reproduction-related organs. In conclusion, the developed method and its software allowed us to identify a short list of presumably lost genes associated with a long lifespan in Euarchontoglires. The predicted lost genes largely demonstrate specific expressions in reproductive organs, which agrees with Williams' hypothesis concerning the reallocation of the physiological resources of the body between self-maintenance and reproduction (transition from r-strategy to К-strategy in the species evolution). The loss of some predicted vomeronasal and olfactory receptor genes in human and naked mole-rat conforms to their specific anatomical features. We suggest that the loss of certain genes in evolution is one of the essential determinants of lifespan. Overall, it is a likely driving force for many aspects of species evolution in vertebrates.

This study demonstrates a clear impact of rapamycin treatment on both the molecular signature associated with senescence and the clinical signs of aging in the skin. These data support the idea that a reduction in the burden of senescent cells underlies these improvements. The results could reflect a modification of the senescent cells present in the skin or a reduction in the number of senescent cells. Although rapamycin has been shown to reduce pro-inflammatory secretions produced by senescent cells, the fact that p16INK4A is reduced suggests that the absolute number of senescent cells in the epidermis is reduced. This implies that rather than simply modifying senescent cells present in the tissue, rapamycin treatment is either reducing the number of cells entering senescence or increasing the clearance of senescent cells. Based on our studies demonstrating that rapamycin prevents the senescence transition and improves functionality in vitro, we favor the concept that rapamycin reduces entry into senescence, but we cannot rule out an additional role for clearance of senescent cells. Whether the reduction in senescent cells is due to reduced entry or increased clearance, a reduction in the burden of senescent cells would be expected to improve functionality.

Senescent cells produce pro-inflammatory cytokines, matrix metalloproteins, and reduced levels of anti-angiogenic factors, creating a secretory profile known as the Senescence-Associated Secretory Phenotype (SASP). Thus, we anticipate that rapamycin treatment reduces inflammatory cytokines in the skin, although the verification of this change represents a technical challenge due to the fact that such cytokines are present in picomolar amounts. One quantifiable aspect of skin biology that is improved by the rapamycin treatment is the incorporation of collagen VII into the basement membrane, which represents a functional measure of skin quality that is improved upon treatment with rapamycin. Collagen VII is essential for a functional skin barrier, and the levels of collagen VII decrease with age and specifically beneath wrinkles. Although the mechanism whereby rapamycin may increase collagen VII protein levels is not clear at this time, the known effects of rapamycin on autophagy and intracellular trafficking of vesicles may allow for intracellular processing of misfolded collagen and increase proper localization at the cell periphery and basement membrane.

A notable aspect of this study is the use of such a low dose of rapamycin (10 μM, or 0.001%) for topical application. Topical treatment with higher concentrations (0.1-1%) has been employed for the treatment of tuberous sclerosis complex (TSC) in adults and children and has shown efficacy. We chose to use rapamycin at a ten-fold lower dose because the concentrations used in TSC patients are intended to inhibit cell growth, while our aim was to improve cell function while maintaining proliferative potential and preventing senescence. The positive impact of our treatment regimen suggests that age-related therapy with rapamycin may be feasible at doses far below those associated with side effects; however, this possibility will require careful evaluation in each specific clinical setting.

Whether in the wake of a stroke, seizure, massive neuroinflammation, or a blow to the head, the endothelial cells of the blood-brain barrier (BBB) respond with remarkable similarity, according to a new study. Researchers reported that the endothelial cells that make up the BBB normally express a suite of genes that distinguishes them from the endothelia of other organs. However, BBB cells damaged in various ways lost this specialized signature, changing over to an expression profile more akin to endothelial cells in other parts of the body. The findings suggest that common mechanisms of BBB dysfunction underlie different brain injuries and diseases. "This raises the possibility that successfully preventing (or increasing) endothelial cell gene-expression changes that occur in one disease may lead to a potential therapy for other types of CNS disorders."

Tasked with shielding the precious brain from toxic insults while allowing crucial nutrients to cross, the blood-brain barrier is highly selective. Ergo, the endothelial cells that line the brain's vessels are highly specialized, forming ultra-tight junctions and mobilizing molecular transporters not typically found in vessels supplying other organs. Disruption of the barrier is thought to play a hand in the pathogenesis of multiple injuries and diseases.

How do brain endothelial cells change in the face of injury or disease? The researchers tracked gene-expression changes following four different insults known to disrupt the barrier: seizures, stroke, trauma, and experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. They then tracked the permeability of the barrier at three time points. In the earliest, or "acute" phase of each injury, the researchers found only minimal disruption of the BBB. However, in the so-called "subacute phase," which was one or two days later depending on the model, the leakiness of the BBB reached its peak. About a month later, in the "chronic phase," the barrier had partially or fully regained its integrity.

Each injury induced a bevy of gene-expression changes in brain endothelial cells. They varied substantially among injuries in the acute phase, but shared striking commonalities in the subacute phase, when the barrier was leakiest. By the chronic phase, gene expression had largely returned to normal in the stroke, seizure, and traumatic brain injury models, but remained highly altered in the EAE model. Interestingly, the researchers found that the genetic signature of the healthy BBB endothelium was most downregulated in the acute phase of traumatic brain injury, and the subacute phase of stroke, seizure, and EAE. Conversely, genes expressed predominantly in endothelial cells outside of the brain were turned up in the brain endothelium at these time points. Together, the findings suggest that while brain endothelial cells may initially respond differently to unique insults, they soon converge on a gene-expression profile that resembles those of endothelial cells in other organs of the body. Among other functions, these gene-expression changes likely ramp up interactions between the endothelium and circulating immune cells.

Many cell signals are normally delivered in an intelligent cell-mediated way, meaning that one cell actually moves through the body until it's quite close to a target cell, before releasing the appropriate signal molecules. This greatly increases the likelihood that only the target cell - and not an "off-target" cell - will receive the signal. However, in various diseases, the delivery of the signal molecule is dysregulated in some way, sometimes because a cell is secreting a signal molecule systemically rather than focally to a target cell. The cell that receives this signal molecule - which it would not have received under normal circumstances - may do something it shouldn't do, which can manifest at the tissue level as disease. But the target cell may in fact be responding in a perfectly appropriate way to an incorrect signal. Most medicine still focuses on tissues and organs, rather than the underlying cells and signal molecules.

In cancer, the main problem is not the existence of cancer cells - which the immune system routinely clears out - but rather that cancer cells sometimes persist long enough to erect an inhibitory shield. The secreted molecules inhibit either the immune system's killer cells or the "death signals" those cells produce. There are times when this type of inhibitory signaling is completely appropriate. For instance, the fetus must inhibit the mother's immune system in order to survive, given that's genetically only half the mother and thus looks like an invader. Cancer not only mimics the process used by the fetus/placenta but employs many of the same molecules to do it.

For anti-aging, one would deplete the various known pathogenic signaling molecules that increase with age. Many of these are inflammatory and are responsible for what's termed inflammaging. We are also designing an approach to deplete immune inhibitors secreted by senescent cells for their defense, as a new generation of senolytic therapy. For the vast majority of non-genetic diseases, the drivers or enablers of the disease are signal molecules or molecular signal inhibitors. All of these targets can be depleted by our approach, without drugs and thus without the side effects of drugs.

The over-expression and aggregation of α-synuclein (αSyn) are linked to the onset and pathology of Parkinson's disease. Native monomeric αSyn exists in an intrinsically disordered ensemble of interconverting conformations, which has made its therapeutic targeting by small molecules highly challenging. Nonetheless, here we successfully target the monomeric structural ensemble of αSyn and thereby identify novel drug-like small molecules that impact multiple pathogenic processes.

Using a surface plasmon resonance high-throughput screen, in which monomeric αSyn is incubated with microchips arrayed with tethered compounds, we identified novel αSyn interacting drug-like compounds. Because these small molecules could impact a variety of αSyn forms present in the ensemble, we tested representative hits for impact on multiple αSyn malfunctions in vitro and in cells including aggregation and perturbation of vesicular dynamics. We thereby identified a compound that inhibits αSyn misfolding and is neuroprotective, multiple compounds that restore phagocytosis impaired by αSyn overexpression, and a compound blocking cellular transmission of αSyn.

Our studies demonstrate that drug-like small molecules that interact with native αSyn can impact a variety of its pathological processes. Thus, targeting the intrinsically disordered ensemble of αSyn offers a unique approach to the development of small molecule research tools and therapeutics for Parkinson's disease.

In a previous study, we proposed that age-related mitochondrial respiration defects observed in elderly subjects are partially due to age-associated downregulation of nuclear-encoded genes, including serine hydroxymethyltransferase 2 (SHMT2), which is involved in mitochondrial one-carbon (1C) metabolism. This assertion is supported by evidence that the disruption of mouse Shmt2 induces mitochondrial respiration defects in mouse embryonic fibroblasts generated from Shmt2-knockout E13.5 embryos experiencing anaemia and lethality.

Here, we elucidated the potential mechanisms by which the disruption of this gene induces mitochondrial respiration defects and embryonic anaemia using Shmt2-knockout E13.5 embryos. The livers but not the brains of Shmt2-knockout E13.5 embryos presented mitochondrial respiration defects and growth retardation. Metabolomic profiling revealed that Shmt2 deficiency induced foetal liver-specific downregulation of 1C-metabolic pathways that create taurine and nucleotides required for mitochondrial respiratory function and cell division, respectively, resulting in the manifestation of mitochondrial respiration defects and growth retardation.

The results in this study also suggest that age-associated downregulation of SHMT2 would furthermore control age-related growth retardations, as well as mitochondrial respiration defects, in human fibroblasts from elderly subjects. Therefore, activation of SHMT2 or uptake of certain supplementary 1C sources, such as formate and glycine, might thwart the manifestation of age-related disorders. By contrast, activation of SHMT2 or intake of these supplements might enhance tumour growth due to the fact that SHMT2 is activated in certain human tumour cells, and that its disruption suppresses tumour growth, as well as respiratory function. Therefore, it appears to be controversial whether the activation of SHMT2 or intake of these supplements extends lifespan by restoring mitochondrial respiratory function and cell division or shortens lifespan by the activation of tumour growth and tumour progression. To resolve this controversial issue, further investigation is required.

Aging poses profound health-related challenges that need to be tackled to reduce the social and economic burden on our aging society. Multidisciplinary perspectives will be of tremendous importance to understand the underlying molecular processes of aging and to accelerate the discovery and development of effective aging interventions. It is therefore indispensable that industry and academia develop deeper cooperation and greater interchange of knowledge and technology. For this purpose, world leading experts from diverse research fields and various sectors came together at the 6th installment of the Aging, Drug Discovery and Artificial Intelligence conference, which was held from the 10th to the 12th September 2019 in Basel as part of the Basel Life Science Week.

Although great progress has been made towards the understanding of aging mechanisms, effective drug interventions are still missing for most age-related disorders. Targeting the aging process contrasts the traditional approach of "one disease-one drug"; thus, multiple challenges need to be overcome, as discussed by Nir Barzilai from the Albert Einstein College of Medicine, NY, USA. In particular, the political attention needs to be further strengthened by highlighting the clinical and economic benefits of aging interventions. However, no party will cover intervention costs without an indication for which simple and reliable biomarkers are still lacking. Towards a resolution of this issue, the Targeting Aging with Metformin (TAME) study driven by Nir Barzilai may represent a proof-of-concept that could pave the way to clinical trials leading to healthy aging.

How can we fill the gap between lab animal research, which has traditionally stopped at murine studies, and human clinical trials? Matt Kaeberlein from the University of Washington, Seattle, USA, and colleagues several years ago initialized the dog aging project to overcome this barrier. Companion animals like dogs as model organisms provide multifarious advantages including a faster aging pace than humans, high genetic diversity, and a shared environment with humans. The dog aging project aims to investigate the influence of genetic and environmental determinants on the life- and healthspan of domestic dogs based on survey, sequencing, blood biochemistry and -omics data collection. Further, the project provides the opportunity to test aging interventions, as already initiated for the mammalian Target Of Rapamycin (mTOR) inhibitor rapamycin. Notably, the completed phase 1 for the rapamycin intervention trial revealed no-side effects and improved cardiac function in treated dogs

Aubrey de Grey from the SENS Research Foundation, Mountain View, California, USA, emphasized that placing the focus on healthspan and not on lifespan will help to rebut societal concerns for longevity investigations. Further, he discussed that human diseases with a higher prevalence at older ages should be treated and explored differentially than communicable diseases. In this regard, he introduced the SENS Research Foundation (SRF) and their concept of maintenance by targeting mechanisms that mitigate cellular damage accumulating during aging. Notably, treatments of age-related diseases directed by spinouts of SRF aim to increase the healthspan of elderly - increased longevity is considered as a positive side-effect.

Researchers examined how physical activity affects the activity of bone marrow, specifically hematopoietic stem and progenitor cells (HSPCs). HSPCs can turn into any type of blood cell, including white blood cells called leukocytes, which promote inflammation. The body needs leukocytes to defend against infection and remove foreign bodies. But when these cells become overzealous, they start inflammation in places where they shouldn't, including the walls of arteries.

Researchers studied a group of laboratory mice who were housed in cages with treadmills. Some of the mice ran as much as six miles a night on the spinning wheels. Mice in a second group were housed in cages without treadmills. After six weeks, the running mice had significantly reduced HSPC activity and lower levels of inflammatory leukocytes than other mice who simply sat around their cages all day. Exercising caused the mice to produce less leptin, a hormone made by fat tissue that helps control appetite, but also signals HSPCs to become more active and increase production of leukocytes. In two large studies, the team detected high levels of leptin and leukocytes in sedentary humans who have cardiovascular disease linked to chronic inflammation.

Reassuringly, the study found that lowering leukocyte production levels by exercising didn't make the running mice vulnerable to infection. This study underscores the importance of regular physical activity, but further focuses on how mechanisms by which exercise dampens inflammation could lead to novel strategies for preventing heart attacks and strokes.