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Mitochondrial function as a determinant of life span.

Lanza IR, Nair KS - Pflugers Arch. (2009)

Bottom Line: These effects have yet to be demonstrated in humans, and the duration and level of CR required to extend life span in animals is not realistic in humans.It is proposed that age-related declines in mitochondrial content and function not only affect physical function, but also play a major role in regulation of life span.Regular aerobic exercise and prevention of adiposity by healthy diet may increase healthy life expectancy and prolong life span through beneficial effects at the level of the mitochondrion.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology, Endocrinology Research Unit, Mayo Clinic College of Medicine, Rochester, MN, USA.

ABSTRACT
Average human life expectancy has progressively increased over many decades largely due to improvements in nutrition, vaccination, antimicrobial agents, and effective treatment/prevention of cardiovascular disease, cancer, etc. Maximal life span, in contrast, has changed very little. Caloric restriction (CR) increases maximal life span in many species, in concert with improvements in mitochondrial function. These effects have yet to be demonstrated in humans, and the duration and level of CR required to extend life span in animals is not realistic in humans. Physical activity (voluntary exercise) continues to hold much promise for increasing healthy life expectancy in humans, but remains to show any impact to increase maximal life span. However, longevity in Caenorhabditis elegans is related to activity levels, possibly through maintenance of mitochondrial function throughout the life span. In humans, we reported a progressive decline in muscle mitochondrial DNA abundance and protein synthesis with age. Other investigators also noted age-related declines in muscle mitochondrial function, which are related to peak oxygen uptake. Long-term aerobic exercise largely prevented age-related declines in mitochondrial DNA abundance and function in humans and may increase spontaneous activity levels in mice. Notwithstanding, the impact of aerobic exercise and activity levels on maximal life span is uncertain. It is proposed that age-related declines in mitochondrial content and function not only affect physical function, but also play a major role in regulation of life span. Regular aerobic exercise and prevention of adiposity by healthy diet may increase healthy life expectancy and prolong life span through beneficial effects at the level of the mitochondrion.

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The free radical theory of aging posits that a senescent phenotype is induced by accumulation of oxidative damage resulting from reactive oxygen species. Exercise and caloric restriction are two interventions that induce mitochondrial biogenesis through PGC-1α. Although exercise and CR increase average life expectancy by protecting against age-related comorbidities, only CR has been shown to increase maximal life span; an effect that seems to require the activation of sirtuins
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Fig2: The free radical theory of aging posits that a senescent phenotype is induced by accumulation of oxidative damage resulting from reactive oxygen species. Exercise and caloric restriction are two interventions that induce mitochondrial biogenesis through PGC-1α. Although exercise and CR increase average life expectancy by protecting against age-related comorbidities, only CR has been shown to increase maximal life span; an effect that seems to require the activation of sirtuins

Mentions: Given that many documented adaptations to endurance exercise are the same factors that are impaired with aging, there has been much interest in the utility of exercise to attenuate the deterioration of mitochondrial function with aging. Beneficial adaptations to endurance training seem to be maintained across the life span, as evidenced by robust increases in VO2 peak [98, 109], mitochondrial enzyme activities [20, 98, 109], mitochondrial content [20, 110], protein synthesis rates [111], mtDNA copy number [20], and gene transcripts for mitochondrial proteins [98]. Studies in older rodents provides evidence that exercise training is able to decrease ROS production [112], attenuate DNA oxidative damage, increase the activity of DNA repair processes [113], and increase proteasome activity to aid in the removal of oxidatively damaged proteins [114]. In some cases, these training adaptations in older adults seem to be blunted in comparison to young [115, 116], but several cross-sectional studies of masters level athletes show that markers of muscle mitochondrial function are unchanged with age [19, 117, 118]. Although exercise delays the onset of many mitochondrial changes associated with aging, there are several factors that cannot be attenuated even by vigorous endurance exercise programs. We recently found that chronic (more than 4 years) vigorous endurance training (more than 5 h per week) increased mitochondrial ATP production capacity, increased mitochondrial enzyme activities, increased abundance of mitochondrial proteins, and increased mtDNA abundance [19]. In spite of this high level of physical activity, there remained substantial age-related declines in mtDNA copy number and expression of several mitochondrial respiratory chain proteins. Thus, it seems that exercise can help delay the onset of many age-related detriments, but there is a component of mitochondrial aging that is an inevitable function of chronological age. The aforementioned studies of exercise adaptations with age and other studies involving careful control of health and physical activity patterns [9, 13–15, 117, 119] indicate that environmental and lifestyle factors can account for much of the aging phenotype. We proposed that voluntary physical activities increase muscle mitochondrial capacity which in turn enhances spontaneous activity [120]. In mice, an aerobic exercise program increased muscle mitochondrial DNA abundance and ATP production rate [91] which was associated with increased activity. It appears that maintaining activity by mutation of AGE1 gene increases life span of C. elegans [121]. A similar phenomenon may occur in humans (Fig. 2), but remains to be proven by experimental data. However, although exercise seems to increase average life expectancy by decreasing the incidence of age-related comorbidities, at this point, there is no evidence that exercise increases maximal life span [122–124].Fig. 2


Mitochondrial function as a determinant of life span.

Lanza IR, Nair KS - Pflugers Arch. (2009)

The free radical theory of aging posits that a senescent phenotype is induced by accumulation of oxidative damage resulting from reactive oxygen species. Exercise and caloric restriction are two interventions that induce mitochondrial biogenesis through PGC-1α. Although exercise and CR increase average life expectancy by protecting against age-related comorbidities, only CR has been shown to increase maximal life span; an effect that seems to require the activation of sirtuins
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2801852&req=5

Fig2: The free radical theory of aging posits that a senescent phenotype is induced by accumulation of oxidative damage resulting from reactive oxygen species. Exercise and caloric restriction are two interventions that induce mitochondrial biogenesis through PGC-1α. Although exercise and CR increase average life expectancy by protecting against age-related comorbidities, only CR has been shown to increase maximal life span; an effect that seems to require the activation of sirtuins
Mentions: Given that many documented adaptations to endurance exercise are the same factors that are impaired with aging, there has been much interest in the utility of exercise to attenuate the deterioration of mitochondrial function with aging. Beneficial adaptations to endurance training seem to be maintained across the life span, as evidenced by robust increases in VO2 peak [98, 109], mitochondrial enzyme activities [20, 98, 109], mitochondrial content [20, 110], protein synthesis rates [111], mtDNA copy number [20], and gene transcripts for mitochondrial proteins [98]. Studies in older rodents provides evidence that exercise training is able to decrease ROS production [112], attenuate DNA oxidative damage, increase the activity of DNA repair processes [113], and increase proteasome activity to aid in the removal of oxidatively damaged proteins [114]. In some cases, these training adaptations in older adults seem to be blunted in comparison to young [115, 116], but several cross-sectional studies of masters level athletes show that markers of muscle mitochondrial function are unchanged with age [19, 117, 118]. Although exercise delays the onset of many mitochondrial changes associated with aging, there are several factors that cannot be attenuated even by vigorous endurance exercise programs. We recently found that chronic (more than 4 years) vigorous endurance training (more than 5 h per week) increased mitochondrial ATP production capacity, increased mitochondrial enzyme activities, increased abundance of mitochondrial proteins, and increased mtDNA abundance [19]. In spite of this high level of physical activity, there remained substantial age-related declines in mtDNA copy number and expression of several mitochondrial respiratory chain proteins. Thus, it seems that exercise can help delay the onset of many age-related detriments, but there is a component of mitochondrial aging that is an inevitable function of chronological age. The aforementioned studies of exercise adaptations with age and other studies involving careful control of health and physical activity patterns [9, 13–15, 117, 119] indicate that environmental and lifestyle factors can account for much of the aging phenotype. We proposed that voluntary physical activities increase muscle mitochondrial capacity which in turn enhances spontaneous activity [120]. In mice, an aerobic exercise program increased muscle mitochondrial DNA abundance and ATP production rate [91] which was associated with increased activity. It appears that maintaining activity by mutation of AGE1 gene increases life span of C. elegans [121]. A similar phenomenon may occur in humans (Fig. 2), but remains to be proven by experimental data. However, although exercise seems to increase average life expectancy by decreasing the incidence of age-related comorbidities, at this point, there is no evidence that exercise increases maximal life span [122–124].Fig. 2

Bottom Line: These effects have yet to be demonstrated in humans, and the duration and level of CR required to extend life span in animals is not realistic in humans.It is proposed that age-related declines in mitochondrial content and function not only affect physical function, but also play a major role in regulation of life span.Regular aerobic exercise and prevention of adiposity by healthy diet may increase healthy life expectancy and prolong life span through beneficial effects at the level of the mitochondrion.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology, Endocrinology Research Unit, Mayo Clinic College of Medicine, Rochester, MN, USA.

ABSTRACT
Average human life expectancy has progressively increased over many decades largely due to improvements in nutrition, vaccination, antimicrobial agents, and effective treatment/prevention of cardiovascular disease, cancer, etc. Maximal life span, in contrast, has changed very little. Caloric restriction (CR) increases maximal life span in many species, in concert with improvements in mitochondrial function. These effects have yet to be demonstrated in humans, and the duration and level of CR required to extend life span in animals is not realistic in humans. Physical activity (voluntary exercise) continues to hold much promise for increasing healthy life expectancy in humans, but remains to show any impact to increase maximal life span. However, longevity in Caenorhabditis elegans is related to activity levels, possibly through maintenance of mitochondrial function throughout the life span. In humans, we reported a progressive decline in muscle mitochondrial DNA abundance and protein synthesis with age. Other investigators also noted age-related declines in muscle mitochondrial function, which are related to peak oxygen uptake. Long-term aerobic exercise largely prevented age-related declines in mitochondrial DNA abundance and function in humans and may increase spontaneous activity levels in mice. Notwithstanding, the impact of aerobic exercise and activity levels on maximal life span is uncertain. It is proposed that age-related declines in mitochondrial content and function not only affect physical function, but also play a major role in regulation of life span. Regular aerobic exercise and prevention of adiposity by healthy diet may increase healthy life expectancy and prolong life span through beneficial effects at the level of the mitochondrion.

Show MeSH
Related in: MedlinePlus