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Anti-aging interventions affect lifespan variability in sex, strain, diet and drug dependent fashion.

ABSTRACT: It was recently reported that socio-economic factors related differences in human life expectancy are associated with differences in the variance of age at death. To determine whether anti-aging interventions also alter the variance of longevity, we have analyzed data from mice subjected to treatment with drugs that affect aging or to calorie restriction and from long-lived mutant mice. The relationship of changes in longevity and in longevity variance was found to depend on sex and treatment and apparently also on strain. Increased longevity of male mice treated with effective anti-aging drugs was accompanied by reduced variance of age at death and apparent reduction of early life mortality. Life extension induced by growth-hormone related mutations and calorie restriction tended to increase longevity variance in females only. We conclude that impact of anti-aging interventions on the variance of age at death and distribution of individual lifespans in laboratory mice is treatment-dependent and sexually dimorphic.

SUBMITTER: Bartke A

PROVIDER: S-EPMC6628994 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Anti-aging interventions affect lifespan variability in sex, strain, diet and drug dependent fashion.

Bartke Andrzej A Evans Tracy R TR Musters C J M CJM

Aging 20190601 12

It was recently reported that socio-economic factors related differences in human life expectancy are associated with differences in the variance of age at death. To determine whether anti-aging interventions also alter the variance of longevity, we have analyzed data from mice subjected to treatment with drugs that affect aging or to calorie restriction and from long-lived mutant mice. The relationship of changes in longevity and in longevity variance was found to depend on sex and treatment an ...[more]

PMID: 31235676

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Project description:High-fat diets are associated with increased obesity and metabolic disease in mice and humans. Here we used analysis of variance (ANOVA) to scrutinize a microarray data set consisting of 10 inbred strains of mice from both sexes fed atherogenic high-fat and control chow diets. An overall F-test was applied to the 40 unique groups of strain-diet-sex to identify 15,288 genes with altered transcription. Bootstrapping k-means clustering separated these changes into four strain-dependent expression patterns, including two sex-related profiles and two diet-related profiles. Sex-induced effects correspond to secretion (males) or fat and energy metabolism (females), whereas diet-induced changes relate to neurological processes (chow) or immune response (high-fat). The full set of pairwise contrasts for differences between strains within sex (90 different statistical tests) uncovered 32,379 total changes. These differences were unevenly distributed across strains and between sexes, indicating that strain-specific responses to high-fat diet differ between sexes. Correlations between expression levels and 8 obesity-related traits identified 5,274 associations between transcript abundance and measured phenotypic endpoints. From this number, 2,678 genes are positively correlated with total cholesterol levels and associate with immune-related categories while 2,596 genes are negatively correlated with cholesterol and connect to cholesterol synthesis. Keywords: gene expression analysis, strain comparision, effect of dietary fat, sex-specific effects One group of mice was fed an atherogenic high-fat (30% fat) diet containing cholic acid to increase fat uptake and another was fed a low-fat (6% fat) regular chow diet. Males and females from both diets were studied for mouse strains 129S1/SvImJ, A/J, BALB/cJ, C3H/HeJ, C57BL/6J, CAST/EiJ, DBA/2J, I/LnJ, MRL/MpJ-Tnfrsf6lpr/J, NZB/BINJ, PERA/Ei, and SM/J. All strains were sacrificed between 11- and 13 weeks of age except for CAST and PERA, which were harvested after 50 weeks of age. CAST and PERA were subsequently removed from our analysis based on discrepant harvest age, but can be found in our database (see below). Three replicate animals were used for each combination of diet, strain, and sex, resulting in a total of 120 mice surveyed for gene expression.

Project description:BackgroundThroughout life, physiological homeostasis is challenged and the capacity to cope with such challenges declines with increasing age. In many species, sex differences exist in life expectancy. Sex-specific differences have been related to extrinsic factors like mate competition and/or intrinsic proximate mechanisms such as hormonal changes. In humans, an intrinsic factor related to aging is soluble alpha klotho (?-Kl). Both sexes show an age-related decline in ?-Kl, but throughout life women have higher levels than men of the same age. Sex differences in ?-Kl have been linked to a shorter lifespan, as well as to specific morbidity factors such as atherosclerosis and arteries calcifications. In non-human animals, information on ?-Kl levels is rare and restricted to experimental work. Our cross-sectional study is the first on ?-Kl levels in two long-lived species: bonobos (Pan paniscus) and chimpanzees (Pan troglodytes). As in most mammals, female bonobos and chimpanzees have longer life expectancy than males.MethodsWe measured serum ?-Kl levels of 140 subjects from 16 zoos with an ELISA to examine if ?-Kl levels reflect this difference in life expectancy.ResultsIn both species and in both sexes, ?-Kl levels declined with age suggesting that this marker has potential for aging studies beyond humans. We also found species-specific differences. Adult female bonobos had higher ?-Kl levels than males, a difference that corresponds to the pattern found in humans. In chimpanzees, we found the opposite: males had higher ?-Kl levels than females.ConclusionWe suggest that contrasting sex differences in adult ?-Kl levels mirror the dominance relations between females and males of the two Pan species; and that this might be related to corresponding sex differences in their exposure to stress. In humans, higher cortisol levels were found to be related to lower ?-Kl levels. We conclude that there is great potential for studying aging processes in hominoids, and perhaps also in other non-human primates, by measuring ?-Kl levels. To better understand the causes for sex differences in this aging marker, consideration of behavioural parameters such as competition and stress exposure will be required as well as other physiological markers.

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Anti-aging interventions affect lifespan variability in sex, strain, diet and drug dependent fashion.

Publications

Anti-aging interventions affect lifespan variability in sex, strain, diet and drug dependent fashion.

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