Longevity, aging and rapamycin.
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ABSTRACT:
SUBMITTER: Ehninger D
PROVIDER: S-EPMC4207939 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: Not available
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Project description:Rapamycin increases lifespan in mice, but whether this represents merely inhibition of lethal neoplastic diseases, or an overall slowing in multiple aspects of aging is currently unclear. We report here that many forms of age-dependent change, including alterations in heart, liver, adrenal glands, endometrium, and tendon, as well as age-dependent decline in spontaneous activity, occur more slowly in rapamycin-treated mice, suggesting strongly that rapamycin retards multiple aspects of aging in mice, in addition to any beneficial effects it may have on neoplastic disease. We also note, however, that mice treated with rapamycin starting at 9 months of age have significantly higher incidence of testicular degeneration and cataracts; harmful effects of this kind will guide further studies on timing, dosage, and tissue-specific actions of rapamycin relevant to the development of clinically useful inhibitors of TOR action.
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Project description:Rapamycin treatment is considered a pharmacological intervention with the potential to mimic the longevity benefits of dietary manipulations. However, how rapamycin interacts with nutrition is not fully understood. Here we studied the effect of rapamycin on the longevity of Drosophila under a range of dietary conditions. In diets low in nutrients, rapamycin reduced longevity in a dosage-dependent manner. This dosage effect requires some nutrients as rapamycin has no impact on survival under starvation conditions. Under a balanced diet of yeast and sugar, rapamycin had no repeatable beneficial effect on organismal longevity. These results show that the effect of rapamycin on longevity is sensitive to the nutritional environment and it can reduce lifespan when nutrients are limited.
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Project description:Longevity and healthy aging are among the most complex phenotypes studied to date. The heritability of age at death in adulthood is approximately 25 %. Studies of exceptionally long-lived individuals show that heritability is greatest at the oldest ages. Linkage studies of exceptionally long-lived families now support a longevity locus on chromosome 3; other putative longevity loci differ between studies. Candidate gene studies have identified variants at APOE and FOXO3A associated with longevity; other genes show inconsistent results. Genome-wide association scans (GWAS) of centenarians vs. younger controls reveal only APOE as achieving genome-wide significance (GWS); however, analyses of combinations of SNPs or genes represented among associations that do not reach GWS have identified pathways and signatures that converge upon genes and biological processes related to aging. The impact of these SNPs, which may exert joint effects, may be obscured by gene-environment interactions or inter-ethnic differences. GWAS and whole genome sequencing data both show that the risk alleles defined by GWAS of common complex diseases are, perhaps surprisingly, found in long-lived individuals, who may tolerate them by means of protective genetic factors. Such protective factors may 'buffer' the effects of specific risk alleles. Rare alleles are also likely to contribute to healthy aging and longevity. Epigenetics is quickly emerging as a critical aspect of aging and longevity. Centenarians delay age-related methylation changes, and they can pass this methylation preservation ability on to their offspring. Non-genetic factors, particularly lifestyle, clearly affect the development of age-related diseases and affect health and lifespan in the general population. To fully understand the desirable phenotypes of healthy aging and longevity, it will be necessary to examine whole genome data from large numbers of healthy long-lived individuals to look simultaneously at both common and rare alleles, with impeccable control for population stratification and consideration of non-genetic factors such as environment.
| S-EPMC3898394 | biostudies-literature
Project description:Aging is an inevitable outcome of life, characterized by progressive decline in tissue and organ function and increased risk of mortality. Accumulating evidence links aging to genetic and epigenetic alterations. Given the reversible nature of epigenetic mechanisms, these pathways provide promising avenues for therapeutics against age-related decline and disease. In this review, we provide a comprehensive overview of epigenetic studies from invertebrate organisms, vertebrate models, tissues, and in vitro systems. We establish links between common operative aging pathways and hallmark chromatin signatures that can be used to identify "druggable" targets to counter human aging and age-related disease.
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Project description:Periodontal disease is an age-associated disorder clinically defined by periodontal bone loss, inflammation of the specialized tissues that surround and support the tooth, and microbiome dysbiosis. Currently, there is no therapy for reversing periodontal disease, and treatment is generally restricted to preventive measures or tooth extraction. The FDA-approved drug rapamycin slows aging and extends lifespan in multiple organisms, including mice. Here, we demonstrate that short-term treatment with rapamycin rejuvenates the aged oral cavity of elderly mice, including regeneration of periodontal bone, attenuation of gingival and periodontal bone inflammation, and revertive shift of the oral microbiome toward a more youthful composition. This provides a geroscience strategy to potentially rejuvenate oral health and reverse periodontal disease in the elderly.
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Project description:Increasing evidence suggests an important role for light in regulation of aging and longevity. UV radiation is a mutagen that can promote aging and decrease longevity. In contrast, NIR light has shown protective effects in animal disease models. In invertebrates, visible light can shorten or extend lifespan, depending on the intensity and wavelength composition. Visible light also impacts human health, including retina function, sleep, cancer and psychiatric disorders. Possible mechanisms of visible light include: controlling circadian rhythms, inducing oxidative stress, and acting through the retina to affect neuronal circuits and systems. Changes in artificial lighting (e.g., LEDs) may have implications for human health. It will be important to further explore the mechanisms of how light affects aging and longevity, and how light affects human health.
| S-EPMC6663583 | biostudies-literature
Project description:Various measures incorporated in geriatric assessment have found their way into frailty indices (FIs), which have been used as indicators of survival/mortality and longevity. Our goal is to understand the genetic basis of healthy aging to enhance its evidence base and utility. We constructed a FI as a quantitative measure of healthy aging and examined its characteristics and potential for genetic analyses. Two groups were selected from two separate studies. One group (OLLP for offspring of long-lived parents) consisted of unrelated participants at least one of whose parents was age 90 or older, and the other group of unrelated participants (OSLP for offspring of short-lived parents), both of whose parents died before age 76. FI34 scores were computed from 34 common health variables and compared between the two groups. The FI34 was better correlated than chronological age with mortality. The mean FI34 value of the OSLP was 31 % higher than that of the OLLP (P = 0.0034). The FI34 increased exponentially, at an instantaneous rate that accelerated 2.0 % annually in the OLLP (P = 0.024) and 2.7 % in the OSLP (P < < 0.0001) consequently yielding a 63 % larger accumulation in the latter group (P = 0.0002). The results suggest that accumulation of health deficiencies over the life course is not the same in the two groups, likely due to inheritance related to parental longevity. Consistent with this, sib pairs were significantly correlated regarding FI34 scores, and heritability of the FI34 was estimated to be 0.39. Finally, hierarchical clustering suggests that the OLLP and OSLP differ in their aging patterns. Variation in the FI34 is, in part, due to genetic variation; thus, the FI34 can be a phenotypic measure suitable for genetic analyses of healthy aging.
| S-EPMC3776103 | biostudies-literature
Project description:It is proposed that proteins/enzymes be classified into two classes according to their essentiality for immediate survival/reproduction and their function in long-term health: that is, survival proteins versus longevity proteins. As proposed by the triage theory, a modest deficiency of one of the nutrients/cofactors triggers a built-in rationing mechanism that favors the proteins needed for immediate survival and reproduction (survival proteins) while sacrificing those needed to protect against future damage (longevity proteins). Impairment of the function of longevity proteins results in an insidious acceleration of the risk of diseases associated with aging. I also propose that nutrients required for the function of longevity proteins constitute a class of vitamins that are here named "longevity vitamins." I suggest that many such nutrients play a dual role for both survival and longevity. The evidence for classifying taurine as a conditional vitamin, and the following 10 compounds as putative longevity vitamins, is reviewed: the fungal antioxidant ergothioneine; the bacterial metabolites pyrroloquinoline quinone (PQQ) and queuine; and the plant antioxidant carotenoids lutein, zeaxanthin, lycopene, α- and β-carotene, β-cryptoxanthin, and the marine carotenoid astaxanthin. Because nutrient deficiencies are highly prevalent in the United States (and elsewhere), appropriate supplementation and/or an improved diet could reduce much of the consequent risk of chronic disease and premature aging.
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Project description:Dietary restriction (DR) decreases body weight, improves health, and extends lifespan. DR can be achieved by controlling how much and/or when food is provided, as well as by adjusting nutritional composition. Because these factors are often combined during DR, it is unclear which are necessary for beneficial effects. Several drugs have been utilized that target nutrient-sensing gene pathways, many of which change expression throughout the day, suggesting that the timing of drug administration is critical. Here, we discuss how dietary and pharmacological interventions promote a healthy lifespan by influencing energy intake and circadian rhythms.
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