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Deep phenotyping and lifetime trajectories reveal limited effects of longevity regulators on the aging process in C57BL/6J mice.

ABSTRACT: Current concepts regarding the biology of aging are primarily based on studies aimed at identifying factors regulating lifespan. However, lifespan as a sole proxy measure for aging can be of limited value because it may be restricted by specific pathologies. Here, we employ large-scale phenotyping to analyze hundreds of markers in aging male C57BL/6J mice. For each phenotype, we establish lifetime profiles to determine when age-dependent change is first detectable relative to the young adult baseline. We examine key lifespan regulators (putative anti-aging interventions; PAAIs) for a possible countering of aging. Importantly, unlike most previous studies, we include in our study design young treated groups of animals, subjected to PAAIs prior to the onset of detectable age-dependent phenotypic change. Many PAAI effects influence phenotypes long before the onset of detectable age-dependent change, but, importantly, do not alter the rate of phenotypic change. Hence, these PAAIs have limited effects on aging.

SUBMITTER: Xie K

PROVIDER: S-EPMC9652467 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Deep phenotyping and lifetime trajectories reveal limited effects of longevity regulators on the aging process in C57BL/6J mice.

Xie Kan K Fuchs Helmut H Scifo Enzo E Liu Dan D Aziz Ahmad A Aguilar-Pimentel Juan Antonio JA Amarie Oana Veronica OV Becker Lore L da Silva-Buttkus Patricia P Calzada-Wack Julia J Cho Yi-Li YL Deng Yushuang Y Edwards A Cole AC Garrett Lillian L Georgopoulou Christina C Gerlini Raffaele R Hölter Sabine M SM Klein-Rodewald Tanja T Kramer Michael M Leuchtenberger Stefanie S Lountzi Dimitra D Mayer-Kuckuk Phillip P Nover Lena L LL Oestereicher Manuela A MA Overkott Clemens C Pearson Brandon L BL Rathkolb Birgit B Rozman Jan J Russ Jenny J Schaaf Kristina K Spielmann Nadine N Sanz-Moreno Adrián A Stoeger Claudia C Treise Irina I Bano Daniele D Busch Dirk H DH Graw Jochen J Klingenspor Martin M Klopstock Thomas T Mock Beverly A BA Salomoni Paolo P Schmidt-Weber Carsten C Weiergräber Marco M Wolf Eckhard E Wurst Wolfgang W Gailus-Durner Valérie V Breteler Monique M B MMB Hrabě de Angelis Martin M Ehninger Dan D

Nature communications 20221111 1

Current concepts regarding the biology of aging are primarily based on studies aimed at identifying factors regulating lifespan. However, lifespan as a sole proxy measure for aging can be of limited value because it may be restricted by specific pathologies. Here, we employ large-scale phenotyping to analyze hundreds of markers in aging male C57BL/6J mice. For each phenotype, we establish lifetime profiles to determine when age-dependent change is first detectable relative to the young adult bas ...[more]

PMID: 36369285

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Project description:The lifetime effects of space irradiation (IR) on left ventricular (LV) function are unknown. The cardiac effects induced by space-type IR, specifically 5-ion simplified galactic cosmic ray simulation (simGCRsim), are yet to be discovered. Three-month-old, age-matched, male C57BL/6J mice were irradiated with 137Cs gamma (γ; 100, 200 cGy) and simGCRsim (50 and 100 cGy). LV function was assessed via transthoracic echocardiography at 14 and 28 days (early), and at 365, 440, and 660 (late) days post IR. We measured the endothelial function marker brain natriuretic peptide in plasma at three late timepoints. We assessed the mRNA expression of the genes involved in cardiac remodeling, fibrosis, inflammation, and calcium handling in LVs harvested at 660 days post IR. All IR groups had impaired global LV systolic function at 14, 28, and 365 days. At 660 days, 50 cGy simGCRsim-IR mice exhibited preserved LV systolic function with altered LV size and mass. At this timepoint, the simGCRsim-IR mice had elevated levels of cardiac fibrosis, inflammation, and hypertrophy markers Tgfβ1, Mcp1, Mmp9, and βmhc, suggesting that space-type IR may induce the cardiac remodeling processes that are commonly associated with diastolic dysfunction. IR groups showing statistical significance were modeled to calculate the Relative Biological Effectiveness (RBE) and Radiation Effects Ratio (RER). The observed dose-response shape did not indicate a lower threshold at these IR doses. A single full-body IR at doses of 100-200 cGy for γ-IR, and 50-100 cGy for simGCRsim-IR decreases the global LV systolic function in WT mice as early as 14 and 28 days after exposure, and at 660 days post IR. Interestingly, there is an intermediate time point (365 days) where the impairment in LV function is observed. These findings do not exclude the possibility of increased acute or degenerative cardiovascular disease risks at lower doses of space-type IR, and/or when combined with other space travel-associated stressors such as microgravity.

Dataset Information

Deep phenotyping and lifetime trajectories reveal limited effects of longevity regulators on the aging process in C57BL/6J mice.

Publications

Deep phenotyping and lifetime trajectories reveal limited effects of longevity regulators on the aging process in C57BL/6J mice.

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