Fight Aging! Newsletter, June 24th 2019

The first cause of aging that we will address are the damage to our DNA over time. DNA is the medium of information that makes us who we are, the manufacturing program of our body. This information is made up of genes and all genes are grouped together under the name "genome". All this information must be transmitted from one cell to another when they divide to generate daughter cells. And for that, it is necessary to replicate the DNA integrally at each cellular division.

Unfortunately, even this very powerful replication system is not without errors. It has been noted that DNA errors accumulate in life, as many factors influence the stability of the genome. These factors are varied and can be external, such as smoking, sunlight, food ... but also internal, such as replication errors: when your body has to copy the information contained in your DNA, it makes mistakes. These errors can either be repaired, cause cell death, or, and this is the problem, be transmitted to daughter cells.

Fortunately, we have repair systems. Some genes build proteins to repair replication errors, but sometimes the replication errors affect the genes that make these repair systems and, through a snowball effect, there is an exponential growth of problems within the cell. In mice and humans, it has been shown that there is a causal link between DNA damage accumulation and aging. In fact, when the cells in our body divide a large number of times and are carriers of genetic mutations, this causes a dysfunction of the cell that can cause problems at the level of the organ concerned.

Interestingly, it has been shown that during aging, repair systems (such as the PARP protein) become much more abundant in cells, suggesting that our body is aware of the deregulations that come with age and tries to take the necessary steps to fight them. The activity of these repair systems is however dependent on co-enzymes, small molecules that allow them to function. These are essential fuels for our cells whose concentration and recycling decreases with age. Among them, NAD+ is often mentioned, because it is essential to repair mechanisms, but also to mitochondrial health. When these molecules eventually run out, our repair systems no longer work well, leading to serious disruptions, not only in replication but also in other mechanisms, up to and including cell death.

Supplementing with NAD+ may be a good idea to boost our repair systems but it is also possible that cell suicide linked to NAD+ depletion is a protection of the body against cells that have become genetically diseased and that it would be preferable to eliminate. Researchers have used mice, which have been treated to keep a constant level of NAD+ throughout their lives. And not only the treated mice lived healthier lives but they also lived longer than the untreated mice. This shows that, in mice in any case, upregulating NAD+ seems to be a good idea to fight against aging. In humans, as usual, this remains to be proven.

Senescent cells lose their proliferative potential in response to various stresses. They secrete a variety of pro-inflammatory mediators and proteases, gathered in the senescence-associated secretory phenotype (SASP) that engages the immune system to eliminate senescent cells. Senescent cells accumulate in aging organisms, chronic age-related diseases and benign tumors; conversely, elimination of senescent cells contributes to improve health. They also accumulate in tissues affected by atherosclerosis and their elimination strikingly reduces atherogenicity in animal models. Senescence is thus a link between molecular damage and the altered physiology of aging, and targeting SnC using senolytic drugs appears a promising strategy to reduce the burden of age-related chronic inflammatory diseases, including atherosclerosis.

Angiopoietin like-2 (angptl2) is a member of the SASP and is detectable in most organs of adult mice. Angptl2 is expressed by senescent vascular human endothelial cells (EC), but not quiescent or proliferative EC and is atherogenic when infused in young atherosclerotic (ATX) mouse models. We reported that plasma levels of angptl2 are elevated in patients with cardiovascular diseases (CVD), were associated with endothelial dysfunction, and were predictive of major cardiac adverse events and death. Recently, we reported a strong relationship between arterial expression of p21, a cell cycle inhibitor overexpressed in senescent cells and maintaining growth arrest, and circulating levels of angptl2 in atherosclerotic patients. Senescent EC are activated and promote aggregation of leukocytes, the initiating step of atherogenesis. We therefore hypothesized that down-regulation of vascular angptl2, preferentially in the endothelium of severely dyslipidemic ATX mice would promote endothelial repair and slow atherogenesis.

Here, we report that knockdown of vascular angptl2 by a shRNA (shAngptl2), delivered to the vascular cells via a single injection of an AAV1, slowed atheroma progression in ATX mice. Knockdown of angptl2 was associated with a rapid reduction in the expression of EC senescence-associated p21 accompanied by the increase in Bax/Bcl2 ratio as a marker of apoptosis; subsequently, this was associated with endothelial repair as evidenced by the incorporation of endothelial progenitor CD34+ cells. In addition to our pre-clinical results, we show that vascular ANGPTL2 gene expression is correlated with p21 expression and inflammatory cytokines in the internal mammary artery isolated from severely atherosclerotic patients undergoing a coronary artery bypass surgery. Altogether, our data suggest that targeting vascular angptl2 could be senolytic, delaying the progression of atherosclerosis.

The 738 oldest men who participated in the first survey of the population-based Tromsø Study (Tromsø 1) in Norway in 1974 have now had the chance to reach the age of 90 years. The men were also invited to subsequent surveys (Tromsø 2-7, 1979-2016) and have been followed up for all-cause deaths. This study sought to investigate what could be learned from how these men have fared. The men were born in 1925-1928 and similar health-related data from questionnaires, physical examination, and blood samples are available for all surveys. Survival curves over various variable strata were applied to evaluate the impact of individual risk factors and combinations of risk factors on all-cause deaths. At the end of 2018, 118 (16.0%) of the men had reached 90 years of age.

Smoking in 1974 was the strongest single risk factor associated with survival, with observed percentages of men reaching 90 years being 26.3, 25.7, and 10.8 for never, former, and current smokers, respectively. Significant effects on survival were also found for physical inactivity, low income, being unmarried, high blood pressure, and high cholesterol. For men with 0-4 of these risk factors, the percentages reaching 90 years were 33.3, 24.9, 12.4, 14.4, and 1.5, respectively. Quitting smoking and increasing physical activity before 55 years of age improved survival significantly.

The main finding of this study is the huge reduction in observed life length for men with two or more of the risk factors identified in this study, i.e., current smoking, physical inactivity, low income, being unmarried, high blood pressure, or high total cholesterol. Reported in adult mid-life, these risk factors started to take their toll as early as approximately 55 years of age, and over time, more and more lives were lost. The large effect of lifestyle characteristics at adult middle-age was further underlined by the decreasing survival time and smaller number of men reaching 90 years of age that was observed with increasing number of risk factors. Although each of these risk factors alone was associated with premature death, their massive joint effect emphasizes the benefits of eradicating as many of them as possible.

Among the different risk factors underlying Alzheimer's disease (AD), infection might play a role in late-onset AD. Over the past three decades, infectious agents such as bacteria, viruses, fungi, and protozoa have been reported to trigger the development of AD. The infection hypothesis is not a recent idea. In the 1990s, three laboratories from different countries associated the infection with the etiology of AD. Elderly patients infected with herpes simplex virus (HSV)-1 developed toxic accumulation of amyloid β (Aβ) and phosphorylated (p)-tau protein in the brain. In autopsy cases with histopathologically confirmed AD, spirochetes were found in blood, cerebrospinal fluid, and brain tissue. A national representative survey of US residents involving 1,194 patients with 1,520 hospitalizations for infection with severe sepsis revealed that sepsis survivors were independently associated with substantial and persistent new cognitive impairment and functional disability. All of these studies support the notion that infectious etiology might be a causative factor for the inflammatory pathway associated with AD progression.

The accumulation of misfolded amyloid-β (Aβ) in the brain has been proposed to be the critical triggering event in a complex pathophysiological cascade that leads to AD pathology. The additional physiological role of Aβ as an antimicrobial agent in in vitro and in vivo models has been shown. Studies suggested that Aβ oligomerization, which is considered a pathological development in the context of neurodegeneration, may be a necessary step to potentiate the antimicrobial activity of the peptide. These results raised some important questions about the association between AD and microbial infection. The authors also unveiled the mechanism by which Aβ elicits its antimicrobial property. Aβ binds to a microbe and entraps it by forming amyloid fibrils. The presence of microbes serves as an efficient surface for nucleation of amyloid aggregates, thereby raising the possibility of amyloid deposition.

Even so, the findings raise the question of how the protective function of Aβ fails. The possible answer is microglial dysfunction; accumulation of biologically active peptides following an infection might have not been effectively cleared by microglia in the brain of patients with AD. Additionally, Aβ accumulation in the brain may act as an early toxic event in the pathogenesis of AD. The Aβ monomers, soluble and probably nontoxic, would aggregate into different complex assemblies, including soluble oligomers and protofibrils, with various degrees of toxicity. That may spread throughout the brain, and eventually developed into insoluble amyloid fibrils further assembled into amyloid plaques, which are one of the characteristic histological lesions on AD brains.

Recently, the results from three different groups of investigators demonstrated that sepsis, a life-threatening acute organ dysfunction due to a dysregulated host immune response after infection, induces systemic inflammation that exacerbates the accumulation of Aβ and triggers AD progression. these reports suggest that inflammation is a cardinal component of the pathophysiology of sepsis. Thus, the role of inflammation might be associated with the long-term cognitive impairment observed in sepsis survivors.

Although the molecular cascade that links systemic inflammation and neuroinflammation is still enigmatic, the possible modules that occur after infection, which lead to long-term impairment and brain dysfunction that ultimately trigger AD pathology, may include the following: Invading microorganisms escalate the peripheral Aβ load, a necessary step to neutralize and eliminate the pathogen from the peripheral environment. The peripherally produced Aβ and cytokines enter the central nervous system as systemic inflammation is able to increase blood-brain barrier permeability. An increase in RAGE expression during systemic inflammation also facilitates the transport of Aβ to the central compartment. Finally, the entry of foreign substances triggers brain-immune system crosstalk, which in turn leads to activation of microglia / astrocytes and local production of inflammatory mediators and reactive species. Further comprehension of these mechanisms with newer insights is warranted to develop a strategy for the potential advancement of therapeutics for infection-induced AD progression.

Aging and age-related disorders progress through an integration of complex biological processes, and do not allow a simple approach to understand the whole picture, however, evidence indicates the central roles of cellular senescence in the pathogenesis of these conditions. Prevalence of age-associated diseases, including atherosclerotic disorders or heart failure increases with chronological aging, and cells positive for senescent markers are now well recognized to have causal roles for the progression of pathologies in these age-related diseases. In vitro studies showed that exposure of young somatic cells to senescent cells promotes senescence of the young cells, and this is described as the "bystander effect". Pharmacological or genetic depletion of senescent cells contributed to reverse aging phenotype, and suppressed pathologies in chronological as well as age-related disease models.

Adult cardiomyocytes were long thought to be terminally differentiated post-mitotic cells, however, accumulating evidence indicates these cells retain proliferative capacity. It was previously reported that in humans, cardiomyocyte turnover was at a rate of less than 1% per year, and this was demonstrated to decline with aging both in humans and mice. The underlying machinery of diminished cardiomyocyte turnover with aging is yet to be defined, and whether this is attributable to cardiomyocyte senescence is not clear due to the lack of specific senescence markers. In mice, it was reported that chronological aging links with an increase in cardiomyocyte size, together with reactive oxygen species (ROS) production, telomere attrition, and high level of p53 or p16Ink4a expression. In this study, compared to young mice (4 months of age), aged mice (20-22 months of age) exhibited increased left ventricular weight and cardiomyocyte volume, and showed reduction in cardiomyocyte number, together with reduced ventricular function, indicating the pathological roles of cardiomyocyte senescence in the aged heart.

Heart failure can be characterized into two types depending on the level of systolic function. One is described as heart failure with reduced ejection fraction (HFrEF), another is classified as heart failure with preserved ejection fraction (HFpEF), and both types of heart failure are prevalent among elderly persons. In the failing heart, chronic sterile inflammation develops, and this is well recognized to promote cardiac remodeling. Inflammation in coronary microvasculature is now thought to have central roles in the pathogenesis of HFpEF, and it was recently indicated that cellular senescence in endothelial cells may also be involved. When senescence-accelerated mice were fed a high-fat high-salt diet, endothelial cell senescence developed in cardiac tissues, and this coincided with the typical hemodynamic and structural changes of HFpEF. Given that aged and/or obese population has higher prevalence for HFpEF, inhibition of endothelial cell senescence pathway may become a next generation therapy for this untreatable disorder.

Despite the advent of new therapeutic strategies to restore blood flow, we are not yet able to prevent the onset of heart failure following myocardial infarction (MI). Hence, it is a major challenge to identify innovative strategies to restore nutrient supply to the infarcted myocardium, ultimately aimed at regeneration of myocardial functionality. The cellular response following MI is characterized by a rapid recruitment of neutrophils. Their arrival is superseded by the infiltration of classical monocytes, which contribute to clearance of debris. However, this subset also drives robust inflammation, leading to pathological remodeling. In contrast, the appearance of nonclassical monocytes and reparative macrophages marks a turning point between inflammation and its resolution, as these cells govern repair and angiogenesis. At this point, knowledge about mechanisms regulating this cellular switch is scarce.

Annexin A1 (AnxA1) is quickly released upon cellular stress; it acts through Formyl peptide receptor-2 to prevent chemokine-mediated integrin activation, and thus, turns off inflammatory recruitment of myeloid cells. AnxA1 also activates pro-repair mechanisms by activation of Rac1 and NOX1, resulting in enhanced epithelial cell migration after injury. Local intestinal delivery of an AnxA1 fragment encapsulated within polymeric nanoparticles was found to accelerate recovery following experimentally induced colitis. With its central position during the switch from inflammation to resolution, we hypothesized that AnxA1 may be an important cue linking initial myeloid cell recruitment to myocardial repair.

AnxA1 knockout mice showed a reduced cardiac functionality and an expansion of proinflammatory macrophages in the ischemic area. Cardiac macrophages from AnxA1 knockout mice exhibited a dramatically reduced ability to release the proangiogenic mediator vascular endothelial growth factor (VEGF)-A. However, AnxA1 treatment enhanced VEGF-A release from cardiac macrophages, and its delivery in vivo markedly improved cardiac performance. AnxA1 has a direct action on cardiac macrophage polarization toward a pro-angiogenic, reparative phenotype. AnxA1 stimulated cardiac macrophages to release high amounts of VEGF-A, thus inducing neovascularization and cardiac repair.

Biomineralization is the deposition of mineral particles within a proteinaceous organic matrix. In bone, this is an essential physiological process, but extensive pathological calcification of soft tissues, in particular the vasculature, commonly occurs in association with disease. Determining how this complex chemical process is controlled is relevant to both bone development and the treatment of detrimental conditions such as "hardening of the arteries." Despite increased understanding of the cell biological processes involved in biomineralization, the chemical mechanism of mineral nucleation remains elusive.

Studies in vitro have shown that the formation of bone-like ordered mineral deposits around collagen fibrils requires other factors such as additional or substituting mineral ions or non-collagenous biomolecules. This implies that there is cellular control of extracellular matrix (ECM) calcification through the secretion of specific factors, but the nature of these factors remains elusive. In both bone and the vasculature, biomineralization is accompanied by osteogenic differentiation of resident osteoblasts and vascular smooth muscle cells (VSMCs), respectively. Osteogenic differentiation results in increased expression of multifunctional acidic proteins, including the small integrin-binding ligand, N-linked glycoprotein (SIBLING) proteins, and speculation has focused on these "osteogenic" proteins as specialist molecules that may selectively bind calcium ions and provide specificity of interaction with collagen fibrils, these proteins do not have the calcium concentration capacity to induce collagen calcification.

Previously we discovered that poly(ADP-ribose) (PAR) is abundant in the calcifying growth plate of developing fetal bone, which led us to hypothesize that PAR may play a role in biomineralization. PAR is a post-translational modification moiety composed of sugar phosphates that is produced by PAR polymerase (PARP) enzymes and adducted to numerous cellular proteins in a process known as PARylation. Several characteristics of PAR lend support to its possible extracellular role in biomineralization: first, the pyrophosphate groups of PAR are predicted to locally bind calcium ions, potentially to the levels needed for mineral nucleation. Second, PARP1 and PARP2, the dominant PAR-producing enzymes, are expressed in response to DNA damage and oxidative stress, both etiologies associated with vascular calcification. Third, emerging evidence suggests that osteogenic differentiation in calcifying osteoblasts is regulated by PARP activity induced by hydrogen peroxide release from cells. Therefore, we explored whether PAR could control the physicochemical process of mineral formation in the ECM and provide evidence that PAR biosynthesis, induced in part by the cellular DNA damage response (DDR), is a unifying factor in physiological bone and pathological artery calcification.

There is now an emerging international social advocacy movement dedicated to promotion of biomedical research and development to alleviate aging-related morbidity, extend healthy period of life, and improve healthy longevity for the elderly population. It is commonly referred to by the activists as the "longevity movement" or "longevity research and advocacy movement," as well as "healthy life extension movement." It is a "hybrid" between the aged rights advocacy, patient advocacy, and science advocacy, as it emphasizes the need to implement preventive medicine to improve health care for the elderly around the world via enhanced medical scientific research with a special focus on the mechanisms of biological aging.

The goals of the movement, defined by the organizations, initiative groups, and individual activists representing it, are the following: (a) to increase public awareness of the plausibility and desirability to bring the processes of aging under medical control, thus extending healthy human life span, delaying the manifestation of age-related diseases, and improving health in the older age; (b) to foster the improvement of the local and global legislation concerning health across the life course, aging, health and well-being of the elderly, and medical research with a special focus on the mechanisms of aging; (c) to allocate more public funding to fundamental and translational research on the mechanisms of aging and age-related diseases; (d) to increase the interest of the investment industry in supporting biotechnology companies involved in developing innovative drugs and therapies targeting the underlying mechanisms of aging and thus able to prevent, delay, or cure age-related diseases; (e) to promote clinical implementation of the evidence-based medical and lifestyle means to extend healthy human life span.

The movement embraces the recent advances of biomedical science proving the possibility to intervene into the degenerative processes of aging to slow down, delay, prevent, and reverse age-related damage accumulation and seeks to enhance and accelerate such advances. The movement is still young and emerging and is not yet strongly related to other forms of health-care advocacy. But a stronger relation is hoped for.

Mendelian randomisation is a way of showing whether or not individual risk factors actually cause disease, rather than just being associated with it. It uses genetic variants that are already known to be associated with potential risk factors, such as body mass index (BMI) and body fat, as indirect indicators or "proxies" for these risk factors. This enables researchers to discover whether the risk factor is the cause of the disease (rather than the other way around), and reduces bias in results because genetic variants are determined at conception and cannot be affected by subsequent external or environmental factors, or by the development of disease.

Researchers studied 96 genetic variants associated with BMI and body fat mass to estimate their effect on 14 cardiovascular diseases in 367,703 participants of white-British descent in UK Biobank - a UK-based national and international resource containing data on 500,000 people, aged 40-69 years. Using Mendelian randomisation they found that higher BMI and fat mass are associated with an increased risk of aortic valve stenosis and most other cardiovascular diseases, suggesting that excess body fat is a cause of cardiovascular disease.

People who had genetic variants that predict higher BMI were at increased risk of aortic valve stenosis, heart failure, deep vein thrombosis, high blood pressure, peripheral artery disease, coronary artery disease, atrial fibrillation, and pulmonary embolism. For every genetically-predicted 1kg/m2 increase in BMI, the increased risk ranged from 6% for pulmonary embolism to 13% for aortic valve stenosis. (Above a BMI that is considered "healthy" (20-25 kg/m2) every 1 kg/m2 increase in BMI for someone who is 1.7 metres tall (5'7") corresponds to a weight gain of nearly 3 kg)

The Phase 1 clinical trial of UBX0101 is a randomized, double-blind, placebo-controlled study evaluating the safety, tolerability and pharmacokinetics of a single intra-articular injection of UBX0101 in patients diagnosed with moderate to severe painful OA of the knee. UBX0101 is a p53/MDM2 interaction inhibitor that targets selective elimination of senescent cells.

In Part A, 48 patients were randomly assigned to receive one of six dose levels of UBX0101 (between 0.1 mg to 4 mg) or placebo in a 3:1 randomization. Primary endpoints were safety and tolerability. Secondary and exploratory endpoints included plasma pharmacokinetics, synovitis as measured by MRI, pain, and measurement of senescence-associated secretory phenotype (SASP) factors and disease-related biomarkers present in synovial fluid and plasma.

In Part B, 30 patients were randomized to receive UBX0101 (4 mg dose) or placebo in a 2:1 randomization. Primary endpoints were safety and tolerability. Secondary and exploratory endpoints included changes in the levels of SASP factors and disease-related biomarkers present in synovial fluid and plasma, and pain. Synovial fluid samples were obtained at baseline and four weeks post-treatment.

In Part A, UBX0101 was well tolerated up to the maximum administered dose of 4 mg. There were no serious adverse events and no patients discontinued because of an adverse event. There were no dose-dependent adverse events or relevant clinical laboratory findings. The majority (66%) of adverse events were mild. In Part B, UBX0101 was well tolerated at the 4 mg dose. There were no serious adverse events and no patients discontinued because of an adverse event. The majority (75%) of adverse events were mild and there were no relevant clinical laboratory findings.

The study demonstrated that UBX0101 was safe and well-tolerated. Improvement in several clinical measures, including pain, function, as well as modulation of certain SASP factors and disease-related biomarkers was observed after a single dose of UBX0101. In approximately half the biomarkers measured in synovial fluid (treatment versus placebo) modulation was observed consistent with elimination of senescent cells and potential improvement in the tissue environment. Changes were observed in MMPs, tissue remodeling factors, and inflammatory cytokines.

Recent aging theories have proposed various causative biomarkers such as reactive oxygen species, calorie restriction, telomere length, insulin signaling, mitochondrial (mt) DNA mutations, fatty acid composition of membranes, and methylation. To date, the validity of these biomarkers has been examined mainly by investigating their age dependency. However, they are not satisfactory for an accurate description of the aging process, and they seem to interact with each other in a complex way. Thus, it is essential to explain how these biomarkers can show that the survival curve and mortality rate are directly related to longevity. Indeed, the probability of survival drops markedly in individuals over the age of 80, and the mortality rate increases exponentially up to the age of 100.

We here propose a new biomarker to describe the mortality rate and survival curve of the elderly. The basal metabolic rate (BMR) has long been known to decline with age, in line with the Harris-Benedict equation (HBE), which is useful for statistical analysis of a large amount of data. The mass-specific BMR (msBMR; BMR per unit mass) confers the standard normalization of BMR to decrease the variation based on the body weight of individual persons. However, the obtained msBMR still varies among them. We developed an approach in which a universal metabolic rate function of age was derived by renormalizing the msBMR. The first renormalization was attained by incorporating the body mass index (BMI) into the HBE. Interestingly, the variation of the msBMR was thus markedly decreased. We further performed a second renormalization to remove the remaining variation due to individual height by a little readjustment of the BMI. As a result, the renormalized msBMR (RmsBMR) revealed an exponential decline with only age.

The RmsBMR is likely proportional to cellular metabolism and then to the mitochondrial number (mt density) within the standard cell. The mt density was found to decrease very slowly with age. The exponential decay form of this density was shown to be a solution of the transport equation for the mitochondrial dynamical fusion/fission flow. This decay form was proven to be based on the Markov process, although the basic mechanism behind the occurrence of the mitochondrial dysfunction has remained unresolved.

During aging, there is progressive decline in the cell's capacity to eliminate its dysfunctional elements by autophagy. Accumulating evidence has highlighted the decrease in the specific autophagy, or recycling, of dysfunctional mitochondria, known as mitophagy, in aging skeletal muscle. This can result in poor mitochondrial function in the skeletal muscle, and has been closely linked to slow walking speed and poor muscle strength in elderly individuals. Consequently, improving mitochondrial function in elderly people by restoring levels of mitophagy represents a promising approach to halt or delay the development of age-related decline in muscle health.

Urolithin A (UA) is a first-in-class natural food metabolite that stimulates mitophagy and prevents the accumulation of dysfunctional mitochondria with age, thereby maintaining mitochondrial biogenesis and respiratory capacity in cells, and, in the nematode Caenorhabditis elegans, improving mobility and extending lifespan. In rodents, UA improves endurance capacity in young rats and in old mice either fed a healthy diet or placed under conditions of metabolic challenge. Recently, UA was shown to have a favourable safety profile following a battery of standardized toxicological tests.

In this report, we detail the outcome of a first-in-human, randomized, double-blind, placebo-controlled clinical study with UA. We administered UA, either as a single dose or as multiple doses over a 4-week period, to healthy, sedentary elderly individuals. We show that UA has a favourable safety profile (primary outcome). UA was bioavailable in plasma at all doses tested, and 4 weeks of treatment with UA at doses of 500 mg and 1,000 mg modulated plasma acylcarnitines and skeletal muscle mitochondrial gene expression in elderly individuals (secondary outcomes). These observed effects on mitochondrial biomarkers show that UA induces a molecular signature of improved mitochondrial and cellular health following regular oral consumption in humans.

The present study reveals that UA induces a molecular signature response, in both the plasma and skeletal muscle of humans, resembling that observed as a consequence of a regular exercise regimen. It is important to highlight that our earlier work revealed that the stimulation of mitophagy by UA led to an induction of mitochondrial biogenesis and an enhancement of mitochondrial function, resulting in improved aerobic endurance and higher muscle strength in treated rodents. In humans, endurance exercise is well known to trigger mitochondrial biogenesis and fatty acid oxidation in the skeletal muscle to optimize efficient production of ATP by skeletal muscle cells under aerobic conditions. It has also been shown that exercise is a natural means of triggering mitophagy, making it particularly important to maintain an active lifestyle during aging, as it ultimately results in improved mitochondrial function in the muscle.

Neurodegenerative diseases, such as Alzheimer's, Parkinson's and Huntington's disease, affect different regions of the human brain. Despite these regional differences, research has shown that the processes inside cells affected by these diseases have a lot in common. One characteristic of these diseases is that specific proteins start to form aggregates, or deposits, that damage and eventually kill the cell. In Parkinson's disease, it is misfolded forms of a protein known as α-synuclein that are involved. These aggregates can recruit normal forms of α-synuclein, causing the formation of more protein aggregates.

It has long been known that cells that lie close to each other can create small channels (known as gap junction channels) between them. These small channels are built from members of a family of proteins known as connexins. Studies by other scientists have suggested that connexins play a role in other types of disease,. This led researchers to wonder whether connexins can play a similar role in the spread of Parkinson's disease in the brain.

The brain contains more than 10 connexins, but the study suggests that the protein deposits in Parkinson's disease interact with only one of them, Cx32. Details of the process by which the harmful proteins transfer from one cell to a neighbouring cell with the aid of the channel-forming protein remain unclear. The scientists do know that the channel created by connexin is too narrow for the protein aggregates to pass through. They have shown that the aggregates bind to the channel-forming protein Cx32 and sneak into the cell together with it. When the researchers inhibited the formation of channels in cells in culture, absorption of α-synuclein was prevented. In experiments using brain tissue from four deceased patients diagnosed with Parkinson's disease, the scientists observed a direct binding between synuclein and connexin in two of the cases, which suggests that they interact with each other also in the Parkinsonian brain but not in normal brains.

An enzyme called eNAMPT is known to orchestrate a key step in the process cells use to make energy. With age, the body's cells become less and less efficient at producing this fuel - called NAD - which is required to keep the body healthy. Researchers have shown that supplementing eNAMPT in older mice with that of younger mice appears to be one route to boosting NAD fuel production and keeping aging at bay. Unlike other studies focused on transfusing whole blood from young mice to old mice, the researchers increased levels of a single blood component, eNAMPT, and showed its far-reaching effects, including improved insulin production, sleep quality, function of photoreceptors in the eye, and cognitive function in performance on memory tests, as well as increased running on a wheel.

The researchers have also shown other ways to boost NAD levels in tissues throughout the body. Most notably, the researchers have studied the effects of giving oral doses of a molecule called NMN, the chemical eNAMPT produces. NMN is being tested in human clinical trials. "We think the body has so many redundant systems to maintain proper NAD levels because it is so important. Our work and others' suggest it governs how long we live and how healthy we remain as we age. Since we know that NAD inevitably declines with age, whether in worms, fruit flies, mice, or people, many researchers are interested in finding anti-aging interventions that might maintain NAD levels as we get older."

Research has shown that the hypothalamus is a major control center for aging throughout the body, and it is directed in large part by eNAMPT, which is released into the blood from fat tissue. The hypothalamus governs vital processes such as body temperature, thirst, sleep, circadian rhythms, and hormone levels. The researchers have shown that the hypothalamus manufactures NAD using eNAMPT that makes its way to the brain through the bloodstream after being released from fat tissue. They also showed that this eNAMPT is carried in small particles called extracellular vesicles. As levels of eNAMPT in the blood decline, the hypothalamus loses its ability to function properly, decreasing life span.

Levels of eNAMPT in the blood were highly correlated with the number of days the mice lived. More eNAMPT meant a longer life span, and less meant a shorter one. The researchers also showed increased life span with delivering eNAMPT to normal old mice. All mice that received saline solution as a control had died before day 881, about 2.4 years. Of the mice that received eNAMPT, one is still alive as of this writing, surpassing 1,029 days, or about 2.8 years. "We could predict, with surprising accuracy, how long mice would live based on their levels of circulating eNAMPT. We don't know yet if this association is present in people, but it does suggest that eNAMPT levels should be studied further to see if it could be used as a potential biomarker of aging."

Aging decreases skeletal muscle mass and strength, but aerobic and resistance exercise training both maintain skeletal muscle function. NAD+ is a coenzyme for ATP production and a required substrate for enzymes regulating cellular homeostasis. In skeletal muscle, NAD+ is mainly generated by the NAD+ salvage pathway in which nicotinamide phosphoribosyltransferase (NAMPT) is rate-limiting. NAMPT decreases with age in human skeletal muscle, and aerobic exercise training increases NAMPT levels in young men. However, whether distinct modes of exercise training increase NAMPT levels in both young and old people is unknown.

We assessed the effects of 12 weeks of aerobic and resistance exercise training on skeletal muscle abundance of NAMPT, nicotinamide riboside kinase 2 (NRK2), and nicotinamide mononucleotide adenylyltransferase (NMNAT) 1 and 3 in young (≤35 years) and older (≥55 years) individuals. NAMPT in skeletal muscle correlated negatively with age, and VO2peak was the best predictor of NAMPT levels. Moreover, aerobic exercise training increased NAMPT abundance 12% and 28% in young and older individuals, respectively, whereas resistance exercise training increased NAMPT abundance 25% and 30% in young and in older individuals, respectively. None of the other proteins changed with exercise training. In a separate cohort of young and old people, levels of NAMPT, NRK1, and NMNAT1/2 in abdominal subcutaneous adipose tissue were not affected by either age or 6 weeks of high-intensity interval training.

Here we provide evidence that various exercise training modalities completely correct the age-dependent decline in skeletal muscle NAMPT abundance. Conversely, neither age nor exercise training affect levels of adipose tissue NAD+ salvage enzymes. Our findings underscore the importance of regular physical activity to restore skeletal muscle NAD+ salvage capacity with age and have general implications for treatment of metabolic disease.