Genes encoding longevity: from model organisms to humans

Kuningas, Maris; Mooijaart, Simon P.; Heemst, Diana van; Zwaan, Bas J.; Slagboom, P. Eline; Westendorp, Rudi G.J.

doi:10.1111/j.1474-9726.2008.00366.x

Cited by 107 publications

(78 citation statements)

References 133 publications

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“…Furthermore, as emerging cellular mechanisms responsible for aging continue to demonstrate considerable overlap across species, there is increasing evidence that intervention strategies can be effectively evaluated in short-lived animals as a screen for potential human therapies (6). Although there is debate as to whether CR will function in humans as effectively as it does in shorter lived research models (7,8), nonhuman primate data suggest that CR can improve at least the quality of life in our close relatives (9).…”

Section: A S the Quincentennial Of The 1513 Launch Of Ponce Dementioning

confidence: 99%

Dietary Interventions to Extend Life Span and Health Span Based on Calorie Restriction

Minor

Allard

Younts

et al. 2010

The Journals of Gerontology Series A: Biological Sciences and M

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The societal impact of obesity, diabetes, and other metabolic disorders continues to rise despite increasing evidence of their negative long-term consequences on health span, longevity, and aging. Unfortunately, dietary management and exercise frequently fail as remedies, underscoring the need for the development of alternative interventions to successfully treat metabolic disorders and enhance life span and health span. Using calorie restriction (CR)-which is well known to improve both health and longevity in controlled studies-as their benchmark, gerontologists are coming closer to identifying dietary and pharmacological therapies that may be applicable to aging humans. This review covers some of the more promising interventions targeted to affect pathways implicated in the aging process as well as variations on classical CR that may be better suited to human adaptation.

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Section: A S the Quincentennial Of The 1513 Launch Of Ponce Dementioning

confidence: 99%

Dietary Interventions to Extend Life Span and Health Span Based on Calorie Restriction

Minor

Allard

Younts

et al. 2010

The Journals of Gerontology Series A: Biological Sciences and M

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“…They include, but are not limited to, the insulin/IGF-1 pathway, the mTOR pathway, the WNT signaling pathway, and the p53/sestrin signaling pathway. The insulin/IGF-1 signaling cascade comprises insulin/IGF-1, insulin/IGF-1 receptor/DAF-2, insulin/IGF-1 receptor substrate (IRS), phosphatidylinositol 3-kinase, 3-phosphoinositide-dependent protein kinase-1, AKT/ PKB, and the FOXO/DAF-16 transcription factor (8,9). Multiple mutations in components of this signaling pathway extend life span, e.g., mutations in DAF-2 or IRS double the life span of C. elegans (10).…”

Section: Introductionmentioning

confidence: 99%

GSK-3α is a central regulator of age-related pathologies in mice

Zhou¹,

Freeman²,

Ahmad³

et al. 2013

J. Clin. Invest.

155

122

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Aging is regulated by conserved signaling pathways. The glycogen synthase kinase-3 (GSK-3) family of serine/ threonine kinases regulates several of these pathways, but the role of GSK-3 in aging is unknown. Herein, we demonstrate premature death and acceleration of age-related pathologies in the Gsk3a global KO mouse. KO mice developed cardiac hypertrophy and contractile dysfunction as well as sarcomere disruption and striking sarcopenia in cardiac and skeletal muscle, a classical finding in aging. We also observed severe vacuolar degeneration of myofibers and large tubular aggregates in skeletal muscle, consistent with impaired clearance of insoluble cellular debris. Other organ systems, including gut, liver, and the skeletal system, also demonstrated age-related pathologies. Mechanistically, we found marked activation of mTORC1 and associated suppression of autophagy markers in KO mice. Loss of GSK-3α, either by pharmacologic inhibition or Gsk3a gene deletion, suppressed autophagy in fibroblasts. mTOR inhibition rescued this effect and reversed the established pathologies in the striated muscle of the KO mouse. Thus, GSK-3α is a critical regulator of mTORC1, autophagy, and aging. In its absence, aging/senescence is accelerated in multiple tissues. Strategies to maintain GSK-3α activity and/or inhibit mTOR in the elderly could retard the appearance of age-related pathologies. IntroductionAging is usually defined as the progressive loss of function accompanied by decreasing fertility and increasing mortality with advancing age (1). It is a complex biological process controlled by multiple genetic, epigenetic, and environmental factors. In order to explain how aging occurs at the molecular level, numerous theories have been proposed, but as yet, a unifying theory has not emerged. There are four main theories that are accepted more widely. (a) The telomere loss theory proposes that telomere shortening represents a cell-intrinsic mechanism, leading to DNA damage accumulation and activation of DNA damage checkpoints in aging cells. Activation of DNA damage checkpoints in response to telomere dysfunction results in induction of cellular senescence (2-4). (b) The somatic mutation theory states that aging proceeds if somatic mutations and other forms of DNA damage exceed the capacity for DNA repair (5). (c) The mitochondrial theory suggests that accumulation of mutations in mitochondrial DNA with age impairs ATP production, resulting in impaired bioenergetics (4). (d) The waste accumulation theory proposes that aging results from the accumulation of damaged proteins or superfluous or dysfunctional organelles due to age-related impairment of degradative processes, including the ubiquitin-proteasome system and, especially, lysosome-mediated autophagy (6, 7).Many conserved signaling pathways and regulatory proteins are reported to regulate life span and rate of aging of eukaryotic organisms. They include, but are not limited to, the insulin/IGF-1 pathway, the mTOR pathway, the WNT signaling pathway, and the p53/sestrin si...

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“…Much of the variation in patterns of mortality in nature may reflect variation in the ability of organisms to respond to naturally occurring stresses (Hughes and Reynolds, 2005;Parsons, 2007;Vleck et al, 2007;Kuningas et al, 2008;Mangel, 2008) and gene-mediating stress responses, either by avoiding or repairing damage, have been shown to have large effects on lifespan (Schumacher et al, 2008). We have no measures of oxidative or other physiological stressors (Conti, 2008), and how they vary with temperature, in C. maculatus.…”

Section: Discussionmentioning

confidence: 99%

Environmental effects on sex differences in the genetic load for adult lifespan in a seed-feeding beetle

Fox

Stillwell

2009

Heredity

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We have little understanding of how environmental conditions affect the expression of the genetic load for lifespan and adult mortality rates, or how this environmental dependence affect tests of models for the evolution of senescence. We use the seed-feeding beetle, Callosobruchus maculatus, as a model to explore how the inbreeding load (L) affecting adult lifespan varies with rearing conditions (diet and temperature), and how rearing conditions affect tests of the mutation accumulation model of senescence. When reared under benign conditions, there was a large sex difference in inbreeding depression (d) and the inbreeding load (L ¼ 0.51-0.86 lethal equivalents per gamete for females L ¼ B0 for males). This sex difference in L was dependent on temperature, but not on rearing host or heat shock. At both high and low temperatures (relative to intermediate temperature) L increased for males, and L converged for the sexes at low temperature (L ¼ 0.26-0.53 for both sexes). Correlations were small for L between pairs of temperatures, indicating that the genes responsible for the inbreeding load differed between temperatures. In contrast to predictions of the mutation accumulation model of senescence, the agespecific inbreeding load for the adult mortality rate (L u(t) ) did not increase with age in any rearing environment. The genetic load underlying lifespan and adult mortality rates, and large sex differences in the genetic load, is highly dependent on environmental conditions. Estimating the genetic load in benign laboratory environments may be insufficient to predict the genetics underlying lifespan variation in nature where environmental variation is the norm.

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Genes encoding longevity: from model organisms to humans

Cited by 107 publications

References 133 publications

Dietary Interventions to Extend Life Span and Health Span Based on Calorie Restriction

Dietary Interventions to Extend Life Span and Health Span Based on Calorie Restriction

GSK-3α is a central regulator of age-related pathologies in mice

Environmental effects on sex differences in the genetic load for adult lifespan in a seed-feeding beetle

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