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Aging is associated with a decline in physiological function and exercise performance. These effects are mediated, at least in part, by an age-related decrease in the bioavailability of nitric oxide (NO), a ubiquitous gasotransmitter and regulator of myriad physiological processes. The decrease in NO bioavailability with aging is especially apparent in sedentary individuals, whereas older, physically active individuals maintain higher levels of NO with advancing age. Strategies which enhance NO bioavailability (including nutritional supplementation) have been proposed as a potential means of reducing the age-related decrease in physiological function and enhancing exercise performance and may be of interest to a range of older individuals including those taking part in competitive sport. In this brief review we discuss the effects of aging on physiological function and endurance exercise performance, and the potential role of changes in NO bioavailability in these processes. We also provide a summary of current evidence for dietary supplementation with substrates for NO production - including inorganic nitrate and nitrite, l-arginine and l-citrulline - for improving exercise capacity/performance in older adults. Additionally, we discuss the (limited) evidence on the effects of (poly)phenols and other dietary antioxidants on NO bioavailability in older individuals. Finally, we provide suggestions for future research.

Cellular senescence is a driver of many age-related pathologies. There is an active search for pharmaceuticals termed senolytics that can mitigate or remove senescent cells invivo by targeting genes that promote the survival of senescent cells. We utilized single-cell RNA sequencing to identify CRYAB as a robust senescence-induced gene and potential target for senolysis. Using chemical inhibitor screening for CRYAB disruption, we identified 25-hydroxycholesterol (25HC), an endogenous metabolite of cholesterol biosynthesis, as a potent senolytic. We then validated 25HC as a senolytic in mouse and human cells in culture and invivo in mouse skeletal muscle. Thus, 25HC represents a potential class of senolytics, which may be useful in combating diseases or physiologies in which cellular senescence is a key driver.

It is unknown if consumption of a Western diet (WD; high-fat/sucrose), versus a non-WD (healthy diet), accelerates declines in physical function over the adult lifespan, and whether regular voluntary activity attenuates age- and WD-associated declines in function. Accordingly, we studied 4 cohorts of mice that consumed either normal chow [NC] or WD with or without access (sedentary, Sed) to voluntary wheel running [VWR] beginning at 3 mo of age. We assessed coordination, grip strength and endurance every 6 mo throughout life, and measured skeletal muscle mass and inflammation at 3 pre-determined ages (6-7, 13-14 and 19-20 mo). Age-related declines (% change 3-18 mo) in physical function were accelerated in WD-Sed versus NC-Sed (coordination: +47 ± 5%; grip strength: +18 ± 2%; endurance: +32 ± 5%; all p < 0.05). VWR attenuated declines in physical function within diet group (coordination: -31 ± 3% with WD-VWR; -18 ± 2% with NC-VWR; grip strength: -26 ± 2% with WD-VWR; -24 ± 2% with NC-VWR; endurance: -48 ± 4% with WD-VWR; -23 ± 6% with NC-VWR; all p < 0.05). Skeletal muscle mass loss and pro-inflammatory cytokine abundance were exacerbated by WD throughout life (mass: NC-Sed [-]7-28%, WD-Sed [-]17-40%; inflammation: NC-Sed [+]40-65%, WD-Sed [+]40-84%, all p < 0.05 versus NC-Sed), and attenuated by VWR (mass: NC-VWR, [-]0-10%, WD-VWR [-]0-10%; inflammation: NC-VWR [+]0-30%, WD-VWR [+]0-42%, all p < 0.05 versus diet-matched Sed group). Our results depict the temporal impairment of physical function over the lifespan in mice, acceleration of dysfunction with WD, the protective effects of voluntary exercise, and the potential associations with skeletal muscle mass and inflammation.

Cancer is one of the most common age-related diseases, and over one-third of cancer patients will receive chemotherapy. One frequently reported side effect of chemotherapeutic agents like doxorubicin (Doxo) is impaired cognitive function, commonly known as "chemotherapy-induced cognitive impairment (CICI)", which may mimic accelerated brain aging. The biological mechanisms underlying the adverse effects of Doxo on the brain are unclear but could involve mitochondrial dysfunction. Here, we characterized brain (hippocampal) transcriptome and cognitive/behavioral changes in young mice treated with Doxo +/- the mitochondrial therapeutic MitoQ. We found that Doxo altered transcriptome/biological processes related to synaptic transmission and neurotransmitter function, neuronal health and behavior, and that these gene expression changes were: 1) similar to key differences observed in transcriptome data on brain aging; and 2) associated with related, aging-like behavioral differences, such as decreased exploration time and impaired novel object recognition test (NOR, an index of learning/memory) performance. Interestingly, MitoQ partially prevented Doxo-induced transcriptome changes in the brain, but it had no effect on behavior or cognitive function. Collectively, our findings are consistent with the idea that chemotherapeutic agents could induce neuronal/gene expression and behavioral changes similar to those that occur during brain aging. In this context, mitochondrial therapeutics may have potential as treatments for CICI at the biological level, but their effects on behavior/cognitive function require further investigation.

As our world’s population ages, cardiovascular diseases (CVD) will become an increasingly urgent public health problem. A key antecedent to clinical CVD and many other chronic disorders of aging is age-related arterial dysfunction, characterized by increased arterial stiffness and impaired arterial endothelial function. Accumulating evidence demonstrates that diet and nutrition may favorably modulate these arterial functions with aging, but many important questions remain. In this review, we will summarize the available information on dietary patterns and nutritional factors that have been studied for their potential to reduce arterial stiffness and improve endothelial function with age, with an emphasis on: 1) underlying physiological mechanisms, and 2) emerging areas of research on nutrition and arterial aging that may hold promise for preventing age-related CVD.

Adaptation to stress is identified as one of the seven pillars of aging research. Our viewpoint discusses the importance of the distinction between stress resistance and resilience, highlights how integration of physiological principles is critical for further understanding in vivo stress resistance and resilience, and advocates for the use of early warning signs to prevent a tipping point in stress resistance and resilience.

Stiffening of large elastic arteries with age increases the risk of cardiovascular diseases (CVD), but the underlying mechanisms are incompletely understood. We investigated the role of mitochondrial quality control (QC, i.e., mitophagy and biogenesis) in arterial stiffening with aging. In C57BL6 mice, aging was associated with impaired aortic expression of mitochondrial QC mediators, greater activation of the mitochondrial redox/stress sensor p66shc, elevated superoxide production and increased arterial stiffness-as indicated by ~25% higher aortic pulse wave velocity (aPWV). In old mice, supplementation with trehalose, a nutraceutical reported to enhance mitophagy, normalized mitochondrial QC markers, p66shc activation and superoxide production, and reduced aPWV and aortic collagen I (a structural protein that confers stiffness). In vitro experiments suggested that mitochondrial QC processes were enhanced in the aortas from old trehalose-treated mice, and in aortic rings studied ex vivo, both aging and treatment with the mitochondrial stressor rotenone were associated with increases in p66shc activation and intrinsic mechanical stiffness, whereas co-incubation with trehalose prevented these effects. Taken together, these findings suggest that mitochondrial stress/dysfunction as a result of impaired mitochondrial QC contributes to large elastic artery stiffening with age. Enhancing mitochondrial QC with agents such as trehalose may be a novel strategy for reducing age-associated arterial stiffness and CVD.

Arterial aging, characterized by stiffening of large elastic arteries and the development of arterial endothelial dysfunction, increases cardiovascular disease (CVD) risk. We tested the hypothesis that spermidine, a nutrient associated with the anti-aging process autophagy, would improve arterial aging. Aortic pulse wave velocity (aPWV), a measure of arterial stiffness, was ~20% greater in old (O, 28 months) compared with young C57BL6 mice (Y, 4 months, P < 0.05). Arterial endothelium-dependent dilation (EDD), a measure of endothelial function, was ~25% lower in O (P < 0.05 vs. Y) due to reduced nitric oxide (NO) bioavailability. These impairments were associated with greater arterial oxidative stress (nitrotyrosine), superoxide production, and protein cross-linking (advanced glycation end-products, AGEs) in O (all P < 0.05). Spermidine supplementation normalized aPWV, restored NO-mediated EDD and reduced nitrotyrosine, superoxide, AGEs and collagen in O. These effects of spermidine were associated with enhanced arterial expression of autophagy markers, and in vitro experiments demonstrated that vascular protection by spermidine was autophagy-dependent. Our results indicate that spermidine exerts a potent anti-aging influence on arteries by increasing NO bioavailability, reducing oxidative stress, modifying structural factors and enhancing autophagy. Spermidine may be a promising nutraceutical treatment for arterial aging and prevention of age-associated CVD.

We tested the hypothesis that curcumin supplementation would reverse arterial dysfunction and vascular oxidative stress with aging. Young (Y, 4–6 mo) and old (O, 26–28 mo) male C57BL6/N mice were given normal or curcumin supplemented (0.2%) chow for 4 weeks (n = 5–10/group/measure). Large elastic artery stiffness, assessed by aortic pulse wave velocity (aPWV), was greater in O (448 ± 15 vs. 349 ± 15 cm/s) and associated with greater collagen I and advanced glycation end-products and less elastin (all P < 0.05). In O, curcumin restored aPWV (386 ± 15 cm/s), collagen I and AGEs to levels not different vs. Y. Ex vivo carotid artery acetylcholine (ACh)-induced endothelial-dependent dilation (EDD, 79 ± 3 vs. 94 ± 2%), nitric oxide (NO) bioavailability and protein expression of endothelial NO synthase (eNOS) were lower in O (all P < 0.05). In O, curcumin restored NO-mediated EDD (92 ± 2%) to levels of Y. Acute ex vivo administration of the superoxide dismutase (SOD) mimetic TEMPOL normalized EDD in O control mice (93 ± 3%), but had no effect in Y control or O curcumin treated animals. O had greater arterial nitrotyrosine abundance, superoxide production and NADPH oxidase p67 subunit expression, and lower manganese SOD (all P < 0.05), all of which were reversed with curcumin. Curcumin had no effects on Y. Curcumin supplementation ameliorates age-associated large elastic artery stiffening, NO-mediated vascular endothelial dysfunction, oxidative stress and increases in collagen and AGEs in mice. Curcumin may be a novel therapy for treating arterial aging in humans.

We tested the hypothesis that sodium nitrite treatment reverses large elastic artery stiffening in old mice via reductions in collagen I, increases in elastin and/or decreases in advanced glycation endproducts (AGEs) mediated by reduced oxidative stress. Aortic pulse wave velocity (aPWV), a measure of large elastic artery stiffness, was greater in old (26–28 mo) compared with young (4–6 mo) control animals (520 ± 9 vs. 405 ± 6 cm/s, p

A senescent phenotype in endothelial cells is associated with increased apoptosis, reduced endothelial nitric oxide synthase (eNOS) and inflammation, which are implicated in arterial dysfunction and disease in humans. We tested the hypothesis that changes in microRNAs are associated with a senescent phenotype in human aortic endothelial cells (HAEC). Compared with early-passage HAEC, late-passage HAEC had a reduced proliferation rate and increased staining for senescence-associated beta-galactosidase and the tumor suppressor p16(INK4a). Late-passage senescent HAEC had reduced expression of proliferation-stimulating/apoptosis-suppressing miR-21, miR-214 and miR-92 and increased expression of tumor suppressors and apoptotic markers. eNOS-suppressing miR-221 and miR-222 were increased and eNOS protein and eNOS activation (phosphorylation at serine1177) were lower in senescent HAEC. Caveolin-1 inhibiting miR-133a was reduced and caveolin-1, a negative regulator of eNOS activity, was elevated in senescent HAEC. Inflammation-repressing miR-126 was reduced and inflammation-stimulating miR-125b was increased, whereas inflammatory proteins were greater in senescent HAEC Development of a senescent arterial endothelial cell phenotype featuring reduced cell proliferation, enhanced apoptosis and inflammation and reduced eNOS is associated with changes in miRNAs linked to the regulation of these processes. Our results support the hypothesis that miRNAs could play a critical role in arterial endothelial cell senescence. (C) 2011 Elsevier Inc. All rights reserved. (Less)

Short-term caloric restriction (CR) protects the young myocardium against ischemia/reperfusion (I/R) injury through a mechanism involving AMP-activated protein kinase (AMPK). Here we ask whether a life-long CR intervention can extend this protection to the aged myocardium, and whether AMP-activated protein kinase (AMPK) plays a role in that protection. Hearts from ad libitum fed (AL) and life-long calorically restricted (LCR) mice were examined at 30 months of age by 25/90 minute global I/R, with and without AMPK inhibition (AraA). LCR hearts were protected from infarction (AL, 28±4 % vs. LCR, 10±1 %, p < 0.01) and post-ischemic functional deficit (LVDP recovery: AL, 65±8 % vs. LCR, 93±7 %, p < 0.01). Pre-ischemic AraA impaired both of these protective effects (Infarct size: LCR+AraA, 22±4 %; LVDP recovery: LCR+AraA, 82±9 %, both p vs. AL > 0.1). AMPKα phosphorylation was dramatically increased in LCR hearts prior to I/R (AL, 1.18±0.01 vs. LCR, 1.68±0.04, ratio, p < 0.0001), and accompanied by a more modest increase in total AMPKα (AL, 2.18±0.03 vs. LCR, 2.39±0.08 ratio, p < 0.05). These results indicate that life-long caloric restriction profoundly protects the aged heart against I/R injury, and suggest that AMPK may play a role in that protection.

Increased arterial stiffness and impaired vascular endothelial function are the two most clinically important events that occur with vascular ageing in humans. Together they contribute to age-associated increases in systolic hypertension, left ventricular remodeling and diastolic dysfunction, coronary artery and other atherosclerotic vascular diseases, congestive heart failure, and the attendant cardiac events such as myocardial infarction. However, there is marked individual variability in arterial stiffness and endothelial function with advancing age, which suggests modulation by one or, more likely, several biological and/or lifestyle factors. Consistent with this idea, habitual aerobic exercise appears to attenuate or completely prevent these adverse changes. Other factors including sex hormone status, circulating total and low-density lipoprotein-cholesterol levels, total body and abdominal fatness, and dietary sodium intake also appear to influence arterial stiffening and endothelial dysfunction with ageing. It is now clear that a number of physiological factors and lifestyle behaviors collectively determine how much and, perhaps in some cases, if functionally or clinically significant vascular ageing occurs in adult humans. Of these, the existing evidence indicates that habitual aerobic exercise may be the single most important modulatory influence.

Background: Indirect measures of body composition suggest that Hispanic women have an excess prevalence of overweight and obesity compared with white women. Socioeconomic status (SES) is a potentially confounding factor in such studies. Objective: Our aim was to determine whether Hispanic ethnicity is associated with higher total and regional adiposity and lower fat-free mass (FFM) in healthy women across the adult age range. Design: We used a prospective cross-sectional design to examine total and regional body composition in 54 Hispanic women (primarily of Mexican descent) and 56 white women of similar SES. Results: The groups were not significantly different in mean age, body mass, or SES, although the Hispanic women were shorter (P < 0.05). Body mass index (in kg/m 2 ; 25.2 ± 0.5 compared with 23.9 ± 0.5; P < 0.05), percentage body fat (38.4 ± 0.8% compared with 34.9 ± 1.3%: P < 0.05), and total fat mass (25.0 ± I.0 compared with 23.0 ± 1.2 kg; P = 0.10) were or tended to be higher in the Hispanic women. The greater total adiposity of the Hispanic women was primarily the result of higher percentage fat and fat mass in the trunk (P < 0.05); within the trunk region, abdominal and subscapular skinfold thicknesses were 30-40% greater in the Hispanic women (P

We have shown previously that endurance-trained postmenopausal runners demonstrate more favorable coronary heart disease (CHD) risk factors compared with age-matched sedentary women. However, the runners exhibited higher levels of physical activity and lower levels of body fatness, both of which can influence CHD risk factors. To gain insight into the influence of body fatness per se, we studied 38 postmenopausal healthy women: 10 swimmers, 10 runners, and nine obese and nine leaner sedentary subjects matched for age, hormone replacement use, and years postmenopause. Swimmers and runners were further matched for exercise training volume (4.5+/-0.2 v 4.6+/-0.6 h/wk) and relative competitive performance (79%+/-5% v 77+/-3% of age-adjusted world record). Maximal oxygen consumption (VO2max) on the treadmill was lower (P < .01) in swimmers versus runners. Body mass (65.0+/-2.0 v 59.0+/-1.3 kg), percent body fat (29%+/-2% v 23%+/-2%), and waist circumference (79+/-3 v 71+/-1 cm) were greater (P < .01) in swimmers than in runners. There were no significant differences in total caloric intake or dietary composition between swimmers and runners. Insulin sensitivity (via Bergman's minimal model) and fasting plasma concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), glucose, and plasminogen activator inhibitor-1 (PAI-1) activity were not different between the groups. However, plasma high-density lipoprotein cholesterol (HDL-C), HDL2-C, HDL-C/TC, insulin, fibrinogen, fibrin D-dimer, PAI antigen, tissue plasminogen activator (t-PA) activity, and t-PA antigen levels all were less favorable (P < .05) in swimmers versus runners. Daytime, nighttime, and 24-hour systolic blood pressure (SBP) was 6 to 10 mm Hg higher in swimmers compared with runners, but resting blood pressure, 24-hour blood pressure load, and blood pressure variability were not significantly different. Stepwise regression showed that measures of body fatness were the primary independent determinants of most of the metabolic CHD risk factors. When analysis of covariance (ANCOVA) was performed with body fatness as a covariate, differences in CHD risk factors between swimmers and runners were abolished (P=.18 to .90). We conclude that among endurance-trained postmenopausal women matched for training volume and competitive eliteness, higher total and abdominal body fatness is, in general, associated with a less favorable metabolic CHD risk profile. Thus, high levels of habitual aerobic exercise do not appear to negate the deleterious effects of adiposity on the coronary risk profile of healthy middle-aged and older women.

The results of this study support the hypothesis that women who exercise regularly have less adverse changes in plasma lipids and lipoproteins with age than sedentary women. This may contribute to the smaller age-related increase in the incidence of coronary heart disease observed in physically active women.

The purpose of this study was to test the hypothesis that the cardiovascular and sympathoadrenal responses to acute environmental stress are attenuated by exercise training. Furthermore, we tested the hypothesis that the cardiovascular and sympathoadrenal responses to intracerebroventricular (ICV) administration of corticotropin-releasing factor (CRF) would be attenuated by training. Conscious, unrestrained, male Sprague-Dawley rats assigned to either a treadmill trained (16–26 m/min, 30–60 min/day, 5 days/week) or nontrained (16–26 m/min, 10 min/day, 1 day/week) group were studied. After 8–10 weeks of training, maximal oxygen uptake was significantly higher in the trained (108 ± 3 ml/kg/min) vs. the nontrained (94 ± 4 ml/min/kg) group. There were no significant differences in baseline mean arterial pressure, heart rate and plasma catecholamine levels associated with training. Trained rats exhibited significantly attenuated elevations in arterial pressure (20 ± 3 vs. 36 ± 2 mmHg for nontrained) and heart rate (−3 ± 3 vs. 12 ± 5 beats/min for nontrained) in response to acute noise stress. Twenty minutes after ICV administration of CRF, blood pressure (trained = 119 ± 2 mmHg, nontrained = 127 ± 2 mmHg), heart rate (trained = 408 ± 8 beats/min, nontrained = 424 ± 10 beats/min), plasma norepinephrine levels (trained = 757 ± 54 pg/ml, nontrained = 775 ± 100 pg/ml) and plasma epinephrine levels (trained = 266 ± 29 pg/ml, nontrained = 225 ± 42 pg/ml) were significantly elevated in both trained and nontrained groups. CRF-induced elevations of blood pressure, but not heart rate or plasma catecholamine levels, were significantly attenuated in the trained group. These data support the hypothesis that regularly performed exercise is associated with diminished cardiovascular responses to environmental stress. Furthermore, the results indicate that exercise training can alter the cardiovascular response to a central nervous system pharmacologic stimulus in the rat.

To determine whether regular exercise improves left ventricular (LV) contractile function in persons 60 years and older, systolic time intervals (STIs) were measured in 10 healthy men and women (mean age 62 +/- 1 year [+/- standard deviation]) before and after 6 months of intense endurance training. STIs, systolic and diastolic blood pressure (BP) and heart rate (HR) were determined at rest and in response to isometric handgrip exercise. Systolic BP, diastolic BP and HR increased acutely from rest in response to handgrip (p less than 0.002). The indexes of total electromechanical systole and LV ejection time (ET) index increased (p less than 0.01), preejection period (PEP) index increased (p less than 0.05) or remained unchanged and PEP/LVET did not change from values at rest in response to handgrip. Training resulted in an 18% increase in maximal oxygen uptake (p less than 0.01). After training, systolic and diastolic BP were reduced at rest (p less than 0.002) and, along with HR, were lower in response to handgrip (p less than 0.002). However, training did not alter STIs at rest or during handgrip. These findings indicate that healthy persons in their 60s have a normal LV response to isometric exercise. Prolonged, intense endurance training does not alter LV contractile function at rest or in response to isometric exercise. However, training can significantly reduce BP at rest, and markedly lower the HR-systolic BP product attained during acute isometric stress, even in normotensive older subjects.