The fine line between lifespan extension and shortening in response to caloric restriction

Szafranski, Kirk; Mekhail, Karim

doi:10.4161/nucl.27929

Cited by 29 publications

(27 citation statements)

References 124 publications

(182 reference statements)

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“…Yet, the molecular mechanisms underlying the beneficial effects of calorie restriction are still poorly understood. It has been questioned whether the actual decrease in calorie intake or the restriction of varying nutrients accounts for life span modulation by calorie restriction (34).…”

Section: Discussionmentioning

confidence: 99%

Calorie Restriction Prevents Metabolic Aging Caused by Abnormal SIRT1 Function in Adipose Tissues

Cai

Fan

et al. 2014

Diabetes

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Adipose tissue is a pivotal organ determining longevity, due largely to its role in maintaining whole-body energy homeostasis and insulin sensitivity. SIRT1 is a NADdependent protein deacetylase possessing antiaging activities in a wide range of organisms. The current study demonstrates that mice with adipose tissue-selective overexpression of hSIRT1(H363Y), a dominant-negative mutant that disrupts endogenous SIRT1 activity, show accelerated development of metabolic aging. These mice, referred to as Adipo-H363Y, exhibit hyperglycemia, dyslipidemia, ectopic lipid deposition, insulin resistance, and glucose intolerance at a much younger age than their wild-type littermates. The metabolic defects of Adipo-H363Y are associated with abnormal epigenetic modifications and chromatin remodeling in their adipose tissues, as a result of excess accumulation of biotin, which inhibits endogenous SIRT1 activity, leading to increased inflammation, cellularity, and collagen deposition. The enzyme acetyl-CoA carboxylase 2 plays an important role in biotin accumulation within adipose tissues of Adipo-H363Y. Calorie restriction prevents biotin accumulation, abolishes abnormal histone biotinylation, and completely restores the metabolic and adipose functions of Adipo-H363Y. The effects are mimicked by short-term restriction of biotin intake, an approach potentially translatable to humans for maintaining the epigenetic and chromatin remodeling capacity of adipose tissues and preventing aging-associated metabolic disorders.Advancing age is associated with loss of energy balance and deterioration of metabolic functions. In older people, postprandial hyperglycemia is common (1). The prevalence of glucose intolerance and insulin resistance increases progressively and significantly with age (2). The redistribution of fat from subcutaneous depots to visceral compartment and from adipose tissues to ectopic sites plays a critical role in the development of aging-related metabolic abnormalities, in particular type 2 diabetes. Older people exhibit elevated central fat deposition but decreased skeletal muscle mass (referred to as sarcopenic obesity) (3). Preadipocytes isolated from aged animals and humans have a reduced potential to differentiate and replicate, whereas aged adipocytes show a decreased capacity for lipid storage (4). The mechanisms underlying age-associated changes in adipose tissue function and fat distribution remain incompletely understood.SIRT1 is a mammalian ortholog most closely related to SIR2 (silent information regulator 2), a protein identified in Saccharomyces cerevisiae that extends replicative life span (5). Both SIRT1 and SIR2 belong to a conserved family of aging regulators and are NAD-dependent deacetylases that catalyze the removal of acetyl groups from protein substrates (6). In yeast, SIR2 acts as a transcriptional silencer by modulating histone modifications, especially at the mating-type loci and telomeric DNA regions (7). These chromosome domains are analogous to the heterochromatin of multicellular eukaryo...

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Section: Discussionmentioning

confidence: 99%

Calorie Restriction Prevents Metabolic Aging Caused by Abnormal SIRT1 Function in Adipose Tissues

Cai

Fan

et al. 2014

Diabetes

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“…ROS are increased in aged tissues [6] and different lines of evidence corroborate the hypothesis that a decrease in metabolic rate attenuates oxidative damage and extends lifespan [6,7]. Calorie restriction, for example, is a multi-target process that increases life span via acting on different levels: it prevents DNA damage and promotes DNA repair, it increases autophagy, decreases oxidative stress and affects mitochondrial efficiency and energy production [8].…”

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confidence: 57%

MECHANISMS LINKING mtDNA DAMAGE AND AGING

Pickrell

Wang

Pinto

et al. 2013

Free Radical Biology and Medicine

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In the last century, considerable efforts were made to understand the role of mtDNA mutations and of oxidative stress in aging. The classic mitochondrial free radical theory of aging, in which mtDNA mutations cause genotoxic oxidative stress, which in turn creates more mutations, has been a central hypothesis in the field for decades. In the last few years, however, new elements have discredited this original theory. The major source of mitochondrial DNA mutations seems to come from replication errors and failure of the repair mechanisms, and the accumulation of these mutations as observed in aged organisms appears to occur by clonal expansion and are not caused by a reactive oxygen species-dependent vicious cycle.New hypotheses of how age-associated mitochondrial dysfunction may lead to aging are based on the role of reactive oxygen species as signaling molecules and on their role in mediating stress responses to age-dependent damage. Here, we review the changes that mtDNA undergoes during aging, and the past and most recent hypotheses linking these changes to the tissue failure observed in aging.

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“…Although it has been shown that caloric restriction, a method for reducing ROS production, slows aging and extends the maximum life in various animal species [61][62][63], their effects on disease resistance and mortality in primates -the closest man mammals -are not very consistent. A first study of 20 years of follow up in rhesus monkeys in which caloric restriction without malnutrition was used showed a decrease in the incidence of agerelated (diabetes, cancer, cardiovascular disease and cerebral atrophy) [64] diseases.…”

Section: Free Radical Theorymentioning

confidence: 99%

Theories of Human Aging of Molecules to Society

Cabrera¹

2015

MOJI

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Aging is a process of deterioration of physiological functions, time-dependent, leading to homeoestenosis. The causes and mechanisms of this process are not yet fully clarified so have issued numerous theories to explain it.The article reviews the major theories of human aging, while proposing a classification that covers the fundamental mechanisms, including deregulation of the immune response (oxy-inflamm-aging) as one of the most cited today.The theories also include those relating to the psychosocial aspects of aging, taking a holistic approach to this biological process of humans.

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The fine line between lifespan extension and shortening in response to caloric restriction

Cited by 29 publications

References 124 publications

Calorie Restriction Prevents Metabolic Aging Caused by Abnormal SIRT1 Function in Adipose Tissues

Calorie Restriction Prevents Metabolic Aging Caused by Abnormal SIRT1 Function in Adipose Tissues

MECHANISMS LINKING mtDNA DAMAGE AND AGING

Theories of Human Aging of Molecules to Society

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