Roger McCarter

Influence of age, exercise, and dietary restriction on oxidative stress in rats

This study was undertaken to investigate the effects of exercise, dietary restriction (DR) and aging on the formation of reactive oxidant species (ROS), antioxidant defenses, and membrane fluidity. Tests were performed on hepatic microsomes, mitochondria, and cytosol from 9- and 20- month-old male Fischer 344 rats, which were divided into four groups: ad libitum fed, sedentary (AS); restricted, sedentary (RS); ad libitum fed, exercised (AE); and restricted, exercised (RE). Results show that both exercise and DR suppressed microsomal ROS production, but not mitochondrial ROS production, which increased with age in all groups. Exercise and DR increased catalase and glutathione peroxidase (GSH-Px) activities and maintained cytosolic ascorbic acid concentration at high levels. Exercise led to significantly higher levels of cytosolic glutathione (GSH). Activity of cytosolic superoxide dismutase (SOD) remained unchanged, whereas glutathione-s-transferase (GST) activity significantly increased with DR. The fluidity of the mitochondrial membrane from exercised and DR rats deteriorated less with age than the membrane from AS rats. Exercise alone was found to improve fluidity, but was more effective when coupled with DR. These results suggest for the first time that the combination of exercise training and DR is the most effective means of preserving membrane fluidity and suppressing microsomal ROS production.

Time to Talk SENS: Critiquing the Immutability of Human Aging

Aging is a three‐stage process: metabolism, damage, and pathology. The biochemical processes that sustain life generate toxins as an intrinsic side effect. These toxins cause damage, of which a small proportion cannot be removed by any endogenous repair process and thus accumulates. This accumulating damage ultimately drives age‐related degeneration. Interventions can be designed at all three stages. However, intervention in metabolism can only modestly postpone pathology, because production of toxins is so intrinsic a property of metabolic processes that greatly reducing that production would entail fundamental redesign of those processes. Similarly, intervention in pathology is a “losing battle” if the damage that drives it is accumulating unabated. By contrast, intervention to remove the accumulating damage would sever the link between metabolism and pathology, and so has the potential to postpone aging indefinitely. We survey the major categories of such damage and the ways in which, with current or foreseeable biotechnology, they could be reversed. Such ways exist in all cases, implying that indefinite postponement of aging—which we term “engineered negligible senescence”—may be within sight. Given the major demographic consequences if it came about, this possibility merits urgent debate.

Exercise and diet modulate cardiac lipid peroxidation and antioxidant defenses

Free radical metabolism can be altered by several interventions, including dietary restriction (DR) and exercise. Most of the previous work has focused on the liver and skeletal muscle. The following experiments were performed to determine whether long-term DR and chronic exercise affect free radical metabolism and change the status of the antioxidant defenses of the heart. Rats were subjected to DR and/or endurance exercise for 18.5 months and were sacrificed along with their ad lib fed and sedentary controls. Both DR and exercise decreased the malondialdehyde content of cardiac mitochondria, indicating a decrease in lipid peroxidation damage. The antioxidant enzymes in the cytosol, superoxide dismutase, selenium dependent glutathione peroxidase, and glutathione S-transferase were all increased by DR. Catalase activity was unaffected by DR but was increased by exercise. The following results demonstrate that long-term DR and exercise modulate the extent of free radical damage in the heart and enhance the antioxidant defense system.

Physical activity as a factor in the action of dietary restriction on aging: Effects in Fischer 344 rats

Dietary restriction (DR) slows the rate of aging in laboratory rodents but the mechanism of action is unknown. DR is known to induce beneficial effects in a variety of tissues and organ systems. DR also maintains high levels of physical activity over the life span. We tested the hypothesis that lifelong physical activity is an important component of the anti-aging action of DR. Male specific pathogen-free Fischer 344 rats were divided into 4 groups at 6 weeks of age: A: fed ad libitum; AE: fed ad libitum and in cages with running wheels; B: fed 60% ad libitum; BE: fed 60% ad libitum and in cages with running wheels. Running activity and spontaneous cage activity were measured over 24 hours and over the life span. Metabolic rate was measured indirectly by analysis of air entering and leaving cages. AE rats exhibited low levels of running activity and ran very little beyond 6 months of age. In contrast, BE rats sustained high running levels even after all A and AE rats had died. High levels of wheel running did not decrease spontaneous cage activity. Median life span (50% survival) was in the order A = AE < B < BE. Ten percent survival was in the order A = AE < B = BE. BE rats had greatest median life span and also highest specific metabolic rate. Exercise and DR altered pathology: At death BE rats had a high incidence of cardiomyopathy, whereas A and AE rats had high incidence of chronic nephropathy and pituitary tumors. The data indicate that increased physical activity is probably not an important factor in the action of DR on aging.

Long-Term IGF-I Exposure Decreases Autophagy and Cell Viability

A reduction in IGF-I signaling has been found to increase lifespan in multiple organisms despite the fact that IGF-I is a trophic factor for many cell types and has been found to have protective effects against multiple forms of damage in acute settings. The increase in longevity seen in response to reduced IGF-I signaling suggests that there may be differences between the acute and chronic impact of IGF-I signaling. We have examined the possibility that long-term stimulation with IGF-I may have a negative impact at the cellular level using quiescent human fibroblasts. We find that fibroblast cells exposed to IGF-I for 14 days have reduced long-term viability as judged by colony forming assays, which is accompanied by an accumulation of senescent cells. In addition we observe an accumulation of cells with depolarized mitochondria and a reduction in autophagy in the long-term IGF-I treated cultures. An examination of mice with reduced IGF-I levels reveals evidence of enhanced autophagy and fibroblast cells derived from these mice have a larger mitochondrial mass relative to controls indicating that changes in mitochondrial turnover occurs in animals with reduced IGF-I. The results indicate that chronic IGF-I stimulation leads to mitochondrial dysfunction and reduced cell viability.

Tissue specific and non-specific changes in gene expression by aging and by early stage CR

Aging alters the expression of a variety of genes. Calorie restriction (CR), which extends life span in laboratory rodents, also changes gene expression. This study investigated changes in gene expression across three different tissues from the same mouse to examine how aging and early stage CR influence gene expression in different tissues of an organism. Expression profiling of heart, liver, and hypothalamus tissues was done in young (4-6 months) ad libitum fed (AL), young CR (2.5-4.5 months of CR), and old (26-28 months) AL male C57BL/6 mice. Aging significantly altered the expressions of 309, 1819, and 1085 genes in heart, liver, and hypothalamus tissues, respectively. In nine genes, aging altered expression across all three tissues although the regulation directions did not agree across all three tissues for some genes. Early stage CR in young mice significantly changed the expressions of 192, 839, and 100 genes in heart, liver, and hypothalamus tissues, respectively, and seven genes altered expression across all three tissues; three were up regulated and four were down regulated. The results of Gene Ontology (GO) Biological Process analysis indicated up regulation of antigen processing/presentation genes by aging and down regulation of stress response genes by early stage CR in all three tissues. The comparison of the results of aging and short term CR studies showed there were 389 genes, 18 GO biological processes, and 20 GO molecular functions in common.

Age-related changes in skeletal muscle function

This review examines current evidence for the existence of aging processes in skeletal muscle fibers. Experimental data demonstrating changes with age in nerve-muscle interaction, excitation-contraction coupling, mechanical properties and muscle energetics are discussed, with emphasis on factors in addition to aging which might account for the observed results. The effects of dietary restriction, exercise and disease on age-related changes in muscle function are also discussed. Results of recent studies highlight the need to establish the health status of subjects and animals used for aging research as well as the need to obtain data from a wide variety of muscles. Although marked decline of muscle performance with age is documented by early studies, recent work indicates that at least some muscles of healthy individuals and animals do not show an age-related decline in function or an impaired ability to respond to exercise. Decreased physical performance in the elderly may be due to factors extrinsic to aged skeletal muscle fibers. (Aging 2: 27–38, 1990)

Conjugated linoleic acid and chromium lower body weight and visceral fat mass in high-fat-diet-fed mice

More than half of the U.S. population has a body mass index of 25 kg/m2 or more, which classifies them as overweight or obese. Obesity is often associated with comorbidities such as diabetes, cardiovascular diseases, and cancer. CLA and chromium have emerged as major dietary supplements that reduce body weight and fat mass, and increase basal metabolic rate in animal models. However, studies show that CLA induces insulin resistance in mice and in humans, whereas Cr improves insulin sensitivity. Hence, we designed the present study to examine the combined effect of CLA and Cr on body composition and insulin sensitivity in a Balb/c mice (n=10/group) model of high-fat-diet-induced obesity. CLA alone lowered body weight, total body fat mass, and visceral fat mass, the last of which decreased further with the combination of CLA and Cr. This effect was accompanied by decreased serum leptin levels in CLA-fed and CLA+Cr-fed mice, and by higher energy expenditure (EE) and oxygen consumption (OC) in CLA+Cr-fed mice. Serum levels of glucose, insulin, the pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6), as well as insulin resistance index (IRI), decreased with CLA, whereas CLA and Cr in combination had significant effects on insulin and IL-6 concentrations and IRI. In summary, CLA+Cr decreased body weight and fat mass in high-fat-diet-fed mice, which may be associated with decreased leptin levels and higher EE and OC.

Mice Producing Reduced Levels of Insulin-Like Growth Factor Type 1 Display an Increase in Maximum, but not Mean, Life Span

Reduced signaling through the IGF type 1 (IGF-1) receptor increases life span in multiple invertebrate organisms. Studies on mammalian longevity suggest that reducing levels of IGF-1 may also increase life span. However, the data are conflicting and complicated by the physiology of the mammalian neuroendocrine system. We have performed life-span analysis on mice homozygous for an insertion in the Igf1 gene. These mice produce reduced levels of IGF-1 and display a phenotype consistent with a significant decrease in IGF-1. Life-span analysis was carried out at three independent locations. Although the life-span data varied between sites, the maximum life span of the IGF-1-deficient mice was significantly increased and age-specific mortality rates were reduced in the IGF-1-deficient mice; however, mean life span did not differ except at one site, where mean life span was increased in female IGF-1-deficient animals. Early life mortality was noted in one cohort of IGF-1-deficient mice. The results are consistent with a significant role for IGF-1 in the modulation of life span but contrast with the published life-span data for the hypopituitary Ames and Snell dwarf mice and growth hormone receptor null mice, indicating that a reduction in IGF-1 alone is insufficient to increase both mean and maximal life span in mice.

Contractile properties of laryngeal muscles in young and old baboons

Aging is associated with changes in voice and/or laryngeal protective reflexes in humans. To assess the role of the laryngeal muscles in this change, we have examined in vitro thyroarytenoid (vocalis) muscles excised from the larynxes of young and old baboons. Contractile properties, fatigue characteristics, and resting oxygen consumption of these muscles were measured. The results indicate that the thyroarytenoid muscle of the baboon is a fast muscle that is resistant to fatigue. The thyroarytenoid muscles of older baboons contracted more slowly and recovered less rapidly from fatigue induced by prolonged contractions but developed more maximum active tension than thyroarytenoid muscles of young adult baboons. These small differences in the characteristics of thyroarytenoid muscle of older baboons are probably not sufficient to explain observed changes in laryngeal function in the elderly. The results suggest that changes in neural pathways and/or morphology of the larynx may play a larger role in the altered laryngeal function with age.