The circadian rhythm: A key variable in aging?

The determination of age-related transcriptional changes may contribute to the understanding of health and life expectancy. The broad application of results from age cohorts may have limitations. Altering sample sizes per time point or sex, using a single mouse strain or tissue, a limited number of replicates, or omitting the middle of life can bias the surveys. To achieve higher general validity and to identify less distinctive players, bulk RNA sequencing of a mouse cohort, including seven organs of two strains from both sexes of 5 ages, was performed. Machine learning by bootstrapped variable importance and selection methodology (Boruta) was used to identify common aging features where the circadian rhythms (CiR) transcripts appear as promising age markers in an unsupervised analysis. Pathways of 11 numerically analyzed local network clusters were affected and classified into four major gene expression profiles, whereby CiR and proteostasis candidates were particularly conspicuous with partially opposing changes. In a data-based interaction association network, the CiR-proteostasis axis occupies an exposed central position, highlighting its relevance. The computation of 11,830 individual transcript associations provides potential superordinate contributors, such as hormones, to age-related changes, as in CiR. In hormone-sensitive LNCaP cells, short-term supraphysiologic levels of the sex hormones dihydrotestosterone or estradiol increase the expression of the CiR transcript Bhlhe40 and the associated senescence regulator Cdkn2b (p15). According to these findings, the bilateral dysregulation of CiR appears as a fundamental protagonist of aging, whose transcripts could serve as a biological marker and its restoration as a therapeutic opportunity.

Towards a Large-Scale Assessment of the Relationship between Biological and Chronological Aging: The INSPIRE Mouse Cohort.

Aging is the major risk factor for the development of chronic diseases. After decades of research focused on extending lifespan, current efforts seek primarily to promote healthy aging. Recent advances suggest that biological processes linked to aging are more reliable than chronological age to account for an individual's functional status, i.e. frail or robust. It is becoming increasingly apparent that biological aging may be detectable as a progressive loss of resilience much earlier than the appearance of clinical signs of frailty. In this context, the INSPIRE program was built to identify the mechanisms of accelerated aging and the early biological signs predicting frailty and pathological aging. To address this issue, we designed a cohort of outbred Swiss mice (1576 male and female mice) in which we will continuously monitor spontaneous and voluntary physical activity from 6 to 24 months of age under either normal or high fat/high sucrose diet. At different age points (6, 12, 18, 24 months), multiorgan functional phenotyping will be carried out to identify early signs of organ dysfunction and generate a large biological fluids/feces/organs biobank (100,000 samples). A comprehensive correlation between functional and biological phenotypes will be assessed to determine: 1) the early signs of biological aging and their relationship with chronological age; 2) the role of dietary and exercise interventions on accelerating or decelerating the rate of biological aging; and 3) novel targets for the promotion of healthy aging. All the functional and omics data, as well as the biobank generated in the framework of the INSPIRE cohort will be available to the aging scientific community. The present article describes the scientific background and the strategies employed for the design of the INSPIRE Mouse cohort.