Fight Aging! Newsletter, September 14th 2020

Following the recent clinical trial failures by Unity Biotechnology and resTORbio, Buck Institute professor Brian Kennedy feels that a change in approach is potentially needed. "I get the idea that you target aging pathways, but then you try to treat disease because you need to get FDA approval and reimbursement from insurance companies - but if that strategy doesn't work, we've got to stop doing it. I think we should actually try to treat aging for a change."

While Kennedy agrees that effort needs to continue to convince the FDA to recognise aging as a treatable disease, Kennedy also believes that there are alternative approaches that can be employed. "You don't need the FDA to approve your trial, you need an institutional review board to approve your trial. From an academic standpoint, as long as you can convince people that the trial is safe, you can use biomarkers and study the effects of these drugs. So I think if we start generating that kind of data, then it'll be a lot easier to get the FDA on board, and hopefully the rest of the world on board. We need to nail down the foundation here and stop giving people excuses why this won't work. I'm still optimistic about drugs, but if you develop a drug for A and try to treat B, and then you wonder why it doesn't work - I'm starting to feel like the strategy may not work that well."

Of course, if companies are going to run trials on aging, then a clearer consensus is needed on the definition of aging, and Kennedy is encouraged by developments in the various clocks that measure biological age. "There's a bunch of clocks and we don't really know how they relate to each other yet, and how specific clocks relate to specific kinds of age-related disease. There are a lot of questions to answer, but I think that the most advanced clocks are starting to look like good biomarkers. Some may be better than others but I'm very optimistic about these biomarkers."

Recent studies have found that beta-amyloid has antiviral and antimicrobial properties, suggesting a possible link between the immune response against infections and the development of Alzheimer's disease. Researchers have now discovered clear evidence of this link: A protein called IFITM3 that is involved in the immune response to pathogens also plays a key role in the accumulation of beta-amyloid in plaques. IFITM3 alters the activity of an enzyme called gamma-secretase, which chops up precursor proteins into the fragments of beta-amyloid that make up plaques. Researchers found that removing IFITM3 decreased the activity of the gamma-secretase enzyme and, as a result, reduced that number of amyloid plaques that formed in a mouse model of the disease.

Neuroinflammation (inflammation in the brain) has emerged as an important line of inquiry in Alzheimer's disease research. Markers of inflammation, such as certain immune molecules called cytokines, are boosted in Alzheimer's disease mouse models and in the brains of people with Alzheimer's disease. This study is the first to provide a direct link between this inflammation and plaque development - by way of IFITM3.

Scientists know that the production of IFITM3 starts in response to activation of the immune system by invading viruses and bacteria. These observations, combined with the new findings that IFITM3 directly contributes to plaque formation, suggest that viral and bacterial infections could increase the risk of Alzheimer's disease development. Indeed, researchers found that the level of IFITM3 in human brain samples correlated with levels of certain viral infections as well as with gamma-secretase activity and beta-amyloid production. Age is the number one risk factor for Alzheimer's, and the levels of both inflammatory markers and IFITM3 increased with advancing age in mice, the researchers found.

Innate immunity is associated with Alzheimer's disease1, but the influence of immune activation on the production of amyloid-β is unknown. Here we identify interferon-induced transmembrane protein 3 (IFITM3) as a γ-secretase modulatory protein, and establish a mechanism by which inflammation affects the generation of amyloid-β.

Inflammatory cytokines induce the expression of IFITM3 in neurons and astrocytes, which binds to γ-secretase and upregulates its activity, thereby increasing the production of amyloid-β. The expression of IFITM3 is increased with ageing and in mouse models that express familial Alzheimer's disease genes. Furthermore, knockout of IFITM3 reduces γ-secretase activity and the formation of amyloid plaques in a transgenic mouse model (5xFAD) of early amyloid deposition. IFITM3 protein is upregulated in tissue samples from a subset of patients with late-onset Alzheimer's disease that exhibit higher γ-secretase activity. The amount of IFITM3 in the γ-secretase complex has a strong and positive correlation with γ-secretase activity in samples from patients with late-onset Alzheimer's disease. These findings reveal a mechanism in which γ-secretase is modulated by neuroinflammation via IFITM3 and the risk of Alzheimer's disease is thereby increased.

The widespread causative biological effects of cellular senescence in tissue ageing pathology make the therapeutic modulation of senescence an attractive target for a plethora of age-related diseases. Genetic studies positively support this idea, with inducible knockdown of p16 alleviating hallmark features of ageing in progeroid murine models. In fact, the well-documented effects of caloric restriction, which both extends mammalian lifespan and delays the onset of age-related disease, may be a physical manifestation of tissue senescence modulation. Caloric restriction has been shown to reduce cardiac senescence, and senescence in hepatocytes and intestinal crypt cells in vivo.

A considerably more attractive proposition is the use of senescence-targeted drugs, otherwise known as senolytics. These drugs affect unique features of senescent cells, such as resistance to apoptosis. Senescent cells upregulate prosurvival pathways, particularly BCL-2. This opens up drug repurposing opportunities around the numerous BCL-2 inhibitors that were developed for the treatment of cancer. Results have been promising. Targeting BCL-2 in vivo induces apoptosis and thus eliminates senescent cells in the lung following irradiation and throughout the body following irradiation or natural ageing.

Other senolytics that have demonstrated experimental efficacy include the tyrosine kinase inhibitor, Dasatinib, used to treat leukaemia, and the flavonoid p53 activator, Quercetin. Combinatorial treatment with Dasatinib and Quercetin extends lifespan, alleviates frailty, and improves vasomotor function in aged mice. Dasatinib and Quercetin have also shown promise in a phase I trial in diabetic kidney disease patients, where reduced senescent cells and circulating SASP factors were observed following administration. Alternative flavonoids are now being tested for their potential senolytic effects, such as Fisetin, which is able to eliminate senescent cells and, crucially, restore tissue function in aged mice.

The importance of transient senescence for effective healing should not be underestimated. As noted previously, temporary induction of senescence aids rapid tissue reformation. During a normal damage response, these senescent cells are effectively cleared by natural killer cells and macrophages. Nevertheless, in chronic situations, senescent cells persist, likely due to elevated immunosenescence and resulting impaired immunological functions. It follows that treatments to boost immune system function, for instance by aiding senescent cell recognition, could be beneficial in the context of transient senescence and tissue repair. Generally, senescent cells express stimulatory ligands that bind to NK2GD receptors on natural killer cells, thus initiating a killing response. However, senescent fibroblasts in aged skin have recently been shown to express HLA-E, which bypasses recognition and clearance by natural killer and T cells. Here, approaches developed in the cancer field may also be useful, for example engineering T cells to express receptors that target specific cellular (tumour) proteins. Studies to identify and validate new senescent cell receptors will be essential to the development and clinical application of such immune-regulated approaches.

We remain a long way from implementing senescence-targeted treatments for pathological wound healing, yet it is reassuring to see that current senolytic drugs display efficacy across a wide range of tissues and pathologies. In a number of studies, systemic senolytic treatments have been shown to have clear effects in peripheral target tissues across a range of treatment regimens. For example, a single dose of BCL inhibitor, and dosing over consecutive days, was able to reverse irradiation-induced senescence in different tissues. In other work, aged mice showed improved physical performance following a biweekly oral treatment of Dasatinib and Quercetin over 4 months, yet reduced SASP was observed in human ex vivo cultured adipose tissue within 48 h of treatment. Moreover, a single 3 day oral treatment of Dasatinib and Quercetin was able to reduce senescence in the adipose tissue of diabetic patients in a phase I trial. These studies therefore suggest that senolytic treatments not only have rapid effects in target peripheral tissues, but can overcome established tissue senescence.

Experimental studies do show beneficial effects of modulating senescence in the skin. For example, elimination of senescent cells from the epidermis restored proliferative capacity in hair follicle stem cells, known to participate in wound healing. Further, blockade of the potential senescence receptor, CXCR2, directly accelerated healing in human ex vivo skin wounds and diabetic murine wounds in vivo. Here, a CXCR2 antagonist was administered to wounds topically (ex vivo) and subcutaneously (in vivo), suggesting direct delivery to the wound site as a viable administration route. Indeed, elevated CXCR2 has previously been observed in diabetic wounds, and more recently in T cells from human diabetic patients. We note with interest that pharmacological inhibition of CXCR1/2 additionally prevents inflammation-mediated damage to pancreatic islets, thus prohibiting streptozocin-induced diabetes in mice. Therefore, CXCR2 appears a common factor in both the ontology and local pathology of diabetes. Senolytics should certainly be considered for the treatment of human chronic wounds characterised by high levels of senescence. However, given that knockdown of CXCR2 and ablation of senescent cells actually delays acute wound healing, future senescence-targeted therapies should be reserved for the treatment of chronic conditions.

Cell senescence, a state of cell cycle arrest due to the finite capacity of cells to proliferate, also occurs as a result of the accumulation of molecular and cellular damage. Senescent cells secrete an array of cytokines, chemokines, growth factors, and proteases collectively referred to as the senescence-associated secretory phenotype (SASP). The array of SASP proteins includes many proteins that have been shown to be regulated by estrogen and to be secreted by platelets, leukocytes, and vascular endothelium including the metalloproteins (MMPs), tumor necrosis factor-α (TNF-α), ecosinoids, and serotonin. However, other proteins considered to be part of the SASP array (e.g., GDF15, Fas, MIP1α, and TNFR1) may be more specific indicators of the systemic senescent cell burden.

In response to DNA damage, senescence serves as an anticancer mechanism and may also have beneficial functions in embryogenesis, parturition, and tissue repair. However, senescent cells that are not cleared efficiently by the immune system disrupt tissue function, which increases the vulnerability to the onset and progression of a host of age-related diseases, including pulmonary dysfunction, cardiovascular disorders, osteoporosis, neurodegeneration, and diabetes. In part, the deleterious effects of senescent cells are mediated by the SASP. Strategies to remove senescent cells and suppress the SASP are now being pursued as a means to counter age-related diseases and geriatric syndromes.

Estrogen is a steroid hormone implicated in modulating cell senescence. For example, estrogen decreases cell senescence in endothelial progenitor cells, and activates estrogen receptor alpha (ERα) to inhibit cell senescence-like phenotypes in human epithelial cells. Estrogen also slows deficits associated with aging and cell senescence in bone, such as declining bone density. However, little is known regarding how cell senescence might be modified by natural changes in hormone concentrations, such as those that occur during menopause, and how this might be modulated by hormone therapies. This study examined whether menopausal hormone therapies, in the form of oral conjugated equine estrogens (oCEE) and transdermal 17β-estradiol (tE2), altered the circulating levels of a specific set of SASP proteins in women who had undergone natural menopause.

Growth differentiation factor 15 (GDF15), tumor necrosis factor receptor 1 (TNFR1), FAS, and macrophage inflammatory protein 1α (MIP1α) were measured in serum. Results were compared among menopausal women participating in the Kronos Early Estrogen Prevention Study randomized to either placebo (n = 38), oral conjugated equine estrogen (oCEE, n = 37), or transdermal 17β-estradiol (tE2, n = 34). Serum levels of the senescent markers for each treatment were compared to placebo 36 months after randomization. We found that serum levels of GDF15, TNFR1, and FAS, but not MIP1α, were lower in both the oCEE and tE2 groups compared to placebo. Differences in the magnitude of effect of the two active treatments may reflect the differences in circulating levels of estrogen metabolites due to formulation and mode of delivery.

The acute anabolic responses to feeding and exercise were found to be dampened in old subjects compared to their young counterparts, thus limiting their recovery and muscle growth. It has been hypothesized that the blunted increase in protein synthesis following acute muscle loading may influence the smaller gains in lean tissue following resistance exercise training in older adults. As such, supplementation of high-quality protein may improve anabolic response to a single bout of exercise. Specific amino acid supplements are available, in the forms of essential amino acids (EAAs), branched-chain amino acids (BCAAs), and leucine. Leucine-rich EAA supplementation enhanced muscle strength following exercise. It is important to note, however, that prolonged protein supplementation with whey or casein, in the setting of a training program, does not appear to improve the exercise response in elderly patients. β-hydroxy-β-methylbutyrate (HMB), a metabolite of leucine which directly activates mTOR, has also been investigated and increased lean muscle mass and strength in sarcopenic individuals.

Chronic, age-related inflammation in skeletal muscle may play a role in aging-associated muscle loss. NF-κB, a master transcriptional regulator of inflammation, becomes upregulated in skeletal muscle with aging. This has led to investigations of whether NF-κB inhibition using commercially available NSAIDs can improve the maintenance of muscle mass. The efficacy of NF-κB inhibition, using commercially available NSAIDs, on the maintenance of muscle mass and strength in response to exercise has been explored in many clinical studies in elderly patients. A 3-month bout of resistance exercise in elderly patients with knee osteoarthritis, NSAIDs therapy resulted in a mild improvement in muscle strength, however, without hypertrophy. Other studies found that NSAID treatment augmented training-induced improvement in strength with associated muscle hypertrophy and limited muscle catabolism. Others have instead shown that NSAID supplementation does not improve skeletal muscle strength or function during physical training. As such, the use of NSAIDs during exercise remains controversial.

Testosterone has emerged as another potential supplement to exercise for the elderly population. Multiple studies have demonstrated that testosterone levels decrease with age. Testosterone administration to elderly patients increases both muscle mass and maximal voluntary strength in a dose-dependent fashion, possibly by the induction of myogenic gene expression. Despite this assertion, the additional benefits of physiological testosterone replacement in elderly patients remains unclear. A prospective study demonstrated increased upper body strength following testosterone treatment of elderly patients with low to normal serum testosterone, but this treatment did not offer any benefit beyond resistance exercise alone.

The growth hormone (GH) axis is another area that has received attention as a potential supplement for exercise therapy for the elderly. GH is made in the pituitary gland and promotes IGF-1 expression in skeletal muscle. IGF-1, in turn, stimulates the Akt/mTOR pathway which promotes muscle anabolism and protein synthesis in response to exercise. In elderly patients, GH treatment increases lean body mass and decreases fat-to-muscle ratio from baseline, although it is unclear as to whether this was attributable to increased skeletal muscle mass. However, multiple studies have shown that healthy elderly patients do not see any additional benefit in strength or muscle hypertrophy with GH supplementation as compared to exercise alone, even at 6-month follow-up. Despite the integral role of the GH/IGF axis on muscle development or hypertrophy, it does not appear to have a therapeutic benefit in physical training in healthy individuals.

Osteoporosis is a common aged-related disease and is characterized by decrease bone mass and bone mineral density, leading to bone fragility and a higher risk of fractures. Researchers have discovered several risk factors associated with osteoporosis, including genetic and epigenetic factors, hormone imbalance, and stem cell senescence. Bone marrow mesenchymal stem cells (BMMSCs) are a group of cell residual in the bone marrow. They have self-renewal capacity and multilineage differentiation potential. There is considerable data showing that BMMSCs play crucial roles in maintaining bone remodeling, reparation, and regeneration. Importantly, the number of BMMSCs declines and their lineage commitment shifts from osteoblasts to adipocytes with aging leading to an imbalance between bone mass and bone marrow fat. This imbalance is considered to be a hallmark of aged-related bone loss disorder, osteoporosis.

During senescence, mesenchymal stem cells (MSCs) undergo epigenetic and transcriptional changes, including decreased expression of stemness genes, Oct4 and Nanog, and increased age-related genes, p16 and p53. Some adverse factors that trigger MSC senescence have been identified, such as reactive oxygen species (ROS) accumulation, telomere shortening, and epigenetic effectors, including histone deacetylases (HDACs) and DNA methyltransferases (DNMTs). However, the details of the epigenetic regulation network remain elusive and its roles in BMMSCs during aged-related bone loss remain to be established.

HDACs are important epigenetic regulators that control gene transcription by removing acetyl groups. In this study, we report that HDAC9 plays an important role in maintaining the balance between osteogenesis and adipogenesis of BMMSCs during aged-related bone mass loss. Furthermore, we found that the downregulation of HDAC9 could partially reverse the differentiation of aging BMMSCs and bone loss in mice by regulating autophagy. These results suggest that aged-related bone mass loss may be partially controlled by the HDAC9-meditated autophagy of BMMSCs.

Blood pressure medication can prevent heart attacks and strokes - even in people with normal blood pressure. "Greater drops in blood pressure with medication lead to greater reductions in the risk of heart attacks and strokes. This holds true regardless of the starting blood pressure level, in people who previously had a heart attack or stroke, and in people who have never had heart disease."

There has been controversy about whether pharmacological blood pressure lowering is equally beneficial in people with versus without a prior heart attack or stroke, and when blood pressure is below the threshold for hypertension (typically 140/90 mmHg). Evidence from previous studies has been inconclusive, leading to contradictory treatment recommendations around the world. This was the largest - and most detailed - study ever conducted to examine these questions. The researchers combined data on individuals who had participated in a randomised clinical trial and conducted a meta-analysis. The study included 348,854 participants from 48 trials.

Participants were divided into two groups: those with a prior diagnosis of cardiovascular disease and those without. Each group was divided into seven subgroups based on systolic blood pressure at study entry (less than 120, 120-129, 130-139, 140-149, 150-159, 160-169, 170 and above mmHg). Over an average four years of follow-up, each 5 mmHg reduction in systolic blood pressure lowered the relative risk of major cardiovascular events by about 10%. The risks for stroke, ischaemic heart disease, heart failure, and death from cardiovascular disease were reduced by 13%, 7% and 14% and 5%, respectively. Neither the presence of cardiovascular disease nor the level of blood pressure at study entry modified the effect of treatment.

Hearing loss in midlife has been estimated to account for 9% of cases of dementia. Acquired hearing loss is most commonly caused by cochlear damage, while dementia is due to cortical degeneration that typically begins in multimodal cortex. This immediately begs the question of how the two are linked. This is a crucial question from a theoretical perspective, as there are multiple biological and psychological pathways that may link peripheral auditory function to broad-based cortical changes associated with dementia. It also has critical practical implications because while it is difficult, if not impossible, to remediate cortical degradation, hearing loss is widely treatable with hearing aids or cochlear implants. Thus, an understanding of the mechanisms linking the two could have wide-ranging public health importance.

There are a number of possible mechanisms for the relationship between hearing loss and dementia. A first possible mechanism is common pathology affecting the cochlea and ascending auditory pathway (causing hearing loss) and the cortex (causing dementia). Alzheimer's disease (AD)-related pathology has been observed in the retina, but it is not well established as occurring in the cochlea. Transgenic mouse models of AD suggest that AD may be associated with cochlear pathology and hearing loss, but the loss is early onset, unlike the midlife impairment in humans. Vascular pathology can also occur in the cochlea, and this is one of the factors implicated in typical acquired hearing loss. It can also affect the ascending auditory pathway and auditory cortex. Vascular mechanisms are therefore potential contributors to the hearing loss associated with cases of vascular dementia.

A second possible mechanism is that hearing loss leads to the decreased stimulation of cognitive processing. The idea is that auditory deprivation creates an impoverished environment, particularly with the diminishment of speech and language input, that negatively affects brain structure and function. This change in brain structure and function is a risk factor for the subsequent development of dementia. A variety of lines of evidence suggest that listening experience may have a direct impact on the human brain. In parallel to the enriched environment studies with mice, the active listening experience of musicians is associated with positive effects on the structure of auditory cortex and the hippocampus and functional changes in the hippocampus. Piano tuners, expert listeners who spend large amounts of time carrying out a highly specialized form of selective listening, demonstrate hippocampal structural correlates of that experience.

A third mechanism is based on the idea that people with hearing impairment use greater cognitive resources for listening, making these resources unavailable for other aspects of higher cognition when they are "occupied" during listening. "Resources" refers here to the means for cognitive tasks such as attention, working memory, or language processing. There is debate about how cognitive resources are allocated, and the corresponding neural bases. With respect to working memory, for example, there is a question about the extent to which resources may be specifically allocated to objects or represent a distributed resource. Further debate concerns the extent to which working memory resources reflect neuronal or synaptic mechanisms, or both. What is important here, however, is that there is a fixed capacity for many general cognitive operations. These resources may be absorbed when listening becomes challenging, reducing their availability for other aspects of cognition.

A fourth possible explanation focuses on auditory cognitive mechanisms in the medial temporal lobe (MTL) that may be specifically linked to AD pathology in the same region. Although MTL structures are not classically regarded as part of the auditory system, animal models support their role in auditory processing. This mechanism starts from the same idea as the prior mechanism, that hearing loss alters cortical activity, including in the MTL. The critical difference is the incorporation of an interaction between that altered activity and AD pathology. The AD pathology that best correlates with the cognitive phenotype is neurofibrillary change related to tau pathology. The earliest neurofibrillary changes in typical AD are found in MTL structures, particularly the perirhinal cortex, which has a strong functional relationship to the hippocampus. This raises the possibility of an interaction between this pathological process and changes in neuronal activity in MTL structures that occur in hearing impaired individuals.

What area of aging and age-related diseases has Calico's biggest focus at the moment?

Our top-level goal is to develop interventions that delay aging, but to test such interventions, we have to be able to measure aging. This is easier said than done - the gold standard, lifespan, takes a long time and is relatively information-poor. There are molecular and cellular changes that occur with age, but it's not always clear which are the most relevant readouts. We'd like to measure aspects of physiological decline, but current healthspan assays take a lot of time and effort, and even then tend to be pretty noisy. To address those limitations, we've spent a lot of time developing innovative tools and novel analyses for quantifying physiological decline in mouse models. We emphasize automated, longitudinal monitoring and multi-dimensional time-series analysis.

On the intervention side, one area of focus for my lab is IGF signaling. This was a pretty straightforward choice - reduced IGF signaling is the most validated anti-aging intervention known (slows aging from worms to mammals, with the largest effect sizes ever reported). There are challenges with targeting this pathway, of course - dose-limiting toxicity, endocrine feedback, lack of biomarkers, just to name a few - but we think we've identified a viable therapeutic strategy.

What emerging discoveries and techniques is Calico utilising?

I'm excited about using outbred mice for intervention testing. We're clearly not the first people to think of this, but we've embraced the concept. Outbred mice are somewhat more resource-intensive than inbred mice because they have more variability, but we think they're worth it. As we're all painfully aware, many published results fail to replicate. I think that a big fraction of what's being called irreproducibility is actually a lack of generalizability. In other words, the results might repeat under the exact same conditions, but alter those conditions just a little and it's a different answer. For mouse studies, strain background is an important condition, and we worry about results from a single, homozygous-at-all-loci genotypes not being generalizable. Outbred mice help us avoid this

What do you think is the best way to quantify longitudinal decline - are there key biomarkers that you're addressing?

Aging manifests at all levels of biological organization (i.e. molecules, cells, tissues, organs, organ-systems, and whole organisms), and measuring aging at each level has pros and cons. Molecular and cellular data provide mechanistic insight and can point to new therapeutic targets, but it can be hard to know if effects are truly relevant to the organism (e.g. does delaying mutation accumulation delay decline in organ function)? Organ-level and physiological data provide health relevance, but it can be hard to tease out mechanism - good for testing putative targets, less good for target discovery. My lab focuses on developing tools for measuring organism-level decline because we think the state of the art is lacking and robustly testing putative targets is rate-limiting in the field.

Centenarians (exceptionally long-lived individuals - ELLI) are a unique segment of the population, exhibiting long human lifespan and healthspan, despite generally practicing similar lifestyle habits as their peers. We tested disease-associated mutation burden in ELLI genomes by determining the burden of pathogenic variants reported in the ClinVar and HGMD databases using data from whole exome sequencing (WES) conducted in a cohort of ELLI, their offspring, and control individuals without antecedents of familial longevity (n = 1879), all descendent from the founder population of Ashkenazi Jews.

The burden of pathogenic variants did not differ between the three groups. Additional analyses of variants subtypes and variant effect predictor (VEP) biotype frequencies did not reveal a decrease of pathogenic or loss-of-function (LoF) variants in ELLI and offspring compared to the control group. Case-control enrichment analyses of pathogenic variants conducted in ELLI and controls also did not identify significant differences in any of the variants between the groups and polygenic risk scores failed to provide a predictive model. Interestingly, cancer and Alzheimer's disease-associated variants were significantly depleted in ELLI compared to controls, suggesting slower accumulation of mutation. That said, polygenic risk score analysis failed to find any predictive variants among the functional variants tested.

The high similarity in the burden of pathogenic variation between ELLI and individuals without familial longevity supports the notion that extension of lifespan and healthspan in ELLI is not a consequence of pathogenic variant depletion but rather a result of other genomic, epigenomic, or potentially nongenomic properties.

The current evidence for the general population regarding physical activity and mortality is comprehensive and unambiguous. Numerous large cohort studies have consistently demonstrated an inverse relationship between physical activity levels and mortality. Compared with the lower physical activity groups, the risk of premature death was remarkably reduced in the higher physical activity groups. One meta-analysis revealed that per 1 hour increment of moderate-intensity physical activity per week, the relative risk of mortality was reduced by 4%.

In the updated physical activity guidelines for healthy adults from the U.S. Department of Health and Human Services, a clear dose-response association between the volume of physical activity and mortality rates has been shown. The shape of the dose-response curve is characterized by a regressive, non-linear effect, where the greatest difference in mortality rates occurs among inactive and minimally active individuals. For higher physical activity levels, the dose-response curve flattens out. This means that the relative risk of mortality continues to decline with higher volumes of physical activity with no adverse effects on mortality, even at very high levels of physical activity.

The objective of this study was to conduct a systematic review and dose-response meta-analysis of physical activity and mortality in people with selected non-communicable diseases (NCDs). We aimed to define the dose-response relationship between post-diagnosis physical activity and mortality rates for nine NCDs with a high global burden of disease, including low back pain, type 2 diabetes (T2D), osteoarthritis, depressive disorder, chronic obstructive pulmonary disease (COPD), breast cancer, lung cancer, stroke, and ischemic heart disease (IHD).

In total, 28 studies were included in the meta-analysis: 12 for breast cancer, 6 for type 2 diabetes, 8 for ischemic heart disease and 2 for COPD. The linear meta-analysis revealed that each 10 metabolic equivalent task hours increase of physical activity per week was associated with a 22% lower mortality rate in breast cancer patients, 12% in ischemic heart disease patients, 30% in COPD patients, and 4% in type 2 diabetes patients. There was indication of a non-linear association with mortality risk reductions even for low levels of activity, as well as a flattening of the curve at higher levels of activity. Thus higher levels of post-diagnosis physical activity are associated with lower mortality rates in breast cancer, type 2 diabetes, ischemic heart disease, and COPD patients, with indication of a no-threshold and non-linear dose-response pattern.

Aging is an irreversible process, and most organisms can never escape the diversity and accumulation of damage that their own functions generate. To reduce damage, species with a simple organization may opt to discard some damage with a part of the cytoplasm, but this mechanism needs to be investigated in more complex species. Interventions such as parabiosis may partially restore aged organ functions through transfusion of young blood to an old organism. This may be considered as a damage dilution process, where the old blood is diluted by the less damaged young blood. It was shown that, following hematopoietic stem cell transfer, the blood of the recipient follows the epigenomic age of the donor, suggesting a possibility to consistently generate younger blood than the actual age of the organism, if the source of hematopoietic stem cells is a young donor. It is important to emphasize that the transition to a younger age, based on one or more tissues being younger than the rest and younger than the chronological age, does not necessarily mean a longer lifespan for the subject, particularly if the lifespan is limited by a particular dysfunction or disorder that causes death.

Although somatic aging appears at first sight irreversible, we cannot bypass the fact that it is successfully reset to zero from generation to generation, suggesting that, during germline development, embryonic development, or some other phases of life there is a process that rewinds the aging clock. Somatic cell nuclear transfer shows that this rewinding process can be also induced in differentiated cell nuclei. These mechanisms of dilution or repair of damage are currently unclear, although evidence suggests that they may involve a combination of cell division, cell selection, epigenetic remodeling, and global activation of genes, especially those genes for controlling DNA damage. These mechanisms allow cells to dilute even the scarcest molecular species such as functionally abnormal RNA, proteins, harmful metabolites, and those that would not be sensed by a cell. Thus, a combination of cell growth, selection, and proliferation dilutes mild damage, in addition to the removal of damage through specialized detoxification, repair, excretion, preemption, and other approaches. These mechanisms together allow the cells to keep the damage in control.

It should be noted that division and dilution are not necessarily related in the context of proliferation of differentiated somatic cells, as, unlike germ cells or stem cells, these cells may undergo senescence or tumor transformation when proliferating in culture. This suggests that there is a particular relationship between cell division and damage dilution, whose mechanism is not yet understood. We think that this relationship is reflected, for instance, in the differences between early embryonic and aged cells, partially due to their different differentiation states. The former may stay in quiescent stage to avoid further damage or proliferate to select the cells with less damage. Compared to adult cells, embryonic cells specifically experience two waves of global demethylation and re-methylation, establishing the same DNA methylation pattern for every generation. These differences suggest a possibility that certain embryonic cells and somatic cells have different modes and rate of damage accumulation and dilution through proliferation. From the damage perspective, the proliferation of cells with more specialized functions bears higher damage, as more specialized molecules are produced, allowing more side-products to be generated. Furthermore, adult stem cells may overcome the proliferation limit when exposed to a mixed pro-stemness signal. This shows that the combined effect of niche pathways that promote the stemness of the adult stem cells may act similarly to reprogramming. Thus, the difference in the damage accumulation between somatic cells and stem cells may lie, at least in part, in the cell matrix environment in which cells reside. Moreover, the environment may undergo a transition to sacrifice stemness for specific biological functions.

To visualize this stage-shifting concept, we advance a weight-scale metaphor, which we call a "stemness-function" model. We designate the two states as "pro-stemness" and "pro-function" based on the balance between damage production and its removal by proliferation and apoptosis. During early life, organisms remain in a "pro-stemness" state, encouraging cells to proliferate and grow so that the damage is unchecked and does not cause cell cycle arrest. In that state, although stem cells exhibit a limited intrinsic immune function, the function to recognize "self" and "nonself" is not yet fully developed, allowing a lower level of inflammation and an increased potential for regeneration. In contrast, in somatic cells, the damage generation can be sensed easier, triggering the reactions such as the DNA damage repair process, growth arrest, apoptosis, and immune responses. Therefore, organisms must undergo a transition from the "pro-stemness" to "pro-function" states, wherein differentiation and specification of cells are supported. Following this transition, the cells enhance their function in reproduction, damage sensing and apoptosis pathway, complete the immune function, and increase fitness by generating specific biological products related to their functions, while adult stem cells at this stage undergo gradual exhaustion. At this stage, damage accumulation is spontaneous while damage dilution via proliferation is not supported in most cell types. During the process of fertilization or before/after it, this damage gets thoroughly checked, cleared and diluted by the transition to the "pro-stemness" state.

What perturbations might then be expected to delay or reverse aging? If a mild "pro-function" feature is induced in the cells with the "pro-stemness" state, it may extend lifespan as we learn from mild overexpression of certain tumor suppressors. Similarly, the weakened immune system upon rapamycin treatment provides an example that the opposite may also work. On the other hand, if a specific function (supported by a certain gene) that shifts the system toward the "pro-function" state is introduced, it may lead to death or premature aging, caused by a sudden increase in function and damage. This might be the case when tumor-suppressor Tp53 is overexpressed in mice, and the animals show a significantly shorter lifespan. It should be noted, however, that similar cases of Tp53 overexpression in mouse models show an indistinguishable lifespan. Nevertheless, considering that cancer-related deaths are more common in lab mice than in humans and that these risks are limited in these cancer-resistant mouse models, there is still a possibility that the overexpression accelerates aging. Conversely, if a "pro-stemness" signal introduced to cells in the "pro-function" state, it may also cause deleterious effects, resulting in cell death or aberrant immortality. For instance, forcing cell proliferation by expressing oncogenes in fibroblasts promotes tumor transformation.

White matter (WM) hyperintensities (WMHs) are one of the most ubiquitous age-related structural changes observed via MRI, yet they are of unknown etiology. WMHs are presumed to be a consequence of age-related vascular changes. Arterial stiffness is associated with WMHs and is the most influential hemodynamic factor in individuals over the age of 60. Age-related arterial dysfunction is the result of a variety of deleterious changes that include intimal remodeling, increased arterial stiffness, and endothelial dysfunction. Age-related changes in the physical properties of, and the interaction between, macrovasculature and microvasculature contribute to the development of WMHs. For example, large artery stiffening transmits increases in pulsatility, the variation of blood pressure throughout the cardiac cycle, to small cerebral vessels. Excessive pulsatility to small cerebral vessels is associated with WMHs.

While cerebrovascular changes are endemic to aging, older adults show considerable variability in vascular brain health. One variable known to positively impact the brain's vascular health is cardiorespiratory fitness (CRF), a product of regular exercise. However, little is known about the effects of CRF on WMH volume per se. In contrast, higher CRF has been linked to higher WM microstructure in older adults. Since low WM microstructure in normal appearing WM precedes conversion to WMHs, WMHs may also be positively influenced by high CRF. If so, CRF may attenuate the development of WMHs in older adults.

This study explored the effects of CRF on WMH volume in community-dwelling older adults. We further tested the possibility of an interaction between CRF and age on WMH volume. Participants were 76 adults between the ages of 59 and 77 who underwent a maximal graded exercise test and structural brain imaging. Results indicated that age was a predictor of WMH volume. However, an age-by-CRF interaction was observed such that higher CRF was associated with lower WMH volume in older participants. Our findings suggest that higher levels of aerobic fitness may protect cerebrovascular health in older adults.

The vascular endothelium in the brain is an essential part of the blood-brain-barrier (BBB) because of its very tight structure to secure a functional and molecular separation of the brain from the rest of the body and to protect neurons from pathogens and toxins. Impaired transport of metabolites across the BBB due to its increasing dysfunction affects brain health and cognitive functioning, thus providing a starting point of neurodegenerative diseases.

The term "cerebral metabolic syndrome" is proposed to highlight the importance of lifestyle factors in neurodegeneration and to describe the impact of increasing BBB dysfunction on neurodegeneration and dementia, especially in elderly patients. If untreated, the cerebral metabolic syndrome may evolve into dementia. Due to the high energy demand of the brain, impaired glucose transport across the BBB via glucose transporters as GLUT1 renders the brain increasingly susceptible to neurodegeneration. Apoptotic processes are further supported by the lack of essential metabolites of the phosphocholine synthesis.

In Alzheimer's disease, inflammatory and infectious processes at the BBB increase the dysfunction and might be pace-making events. Chronic inflammatory processes of the BBB transmitted to an increasing number of brain areas might cause a lasting build-up of spreading, pore-forming β-amyloid fragments explaining the dramatic progression of the disease.