Multi-omics biomarkers and molecular features of aging, longevity and Alzheimer's disease

SUMMARY: While mammals are characterized by dramatic differences in lifespan, from about 2 years in shrews to more than 200 years in the bowhead whale, how Nature achieves such diversity in the rate of aging is unknown. This also applies to diseases, including Alzheimer’s disease and Alzheimer’s disease related dementias (ADRD), as some species are more susceptible to them than others. Projects 4 aims to uncover the molecular basis for natural changes in longevity and develop and apply tools to quantify these differences at the level of molecular signatures of longevity and biomarkers of aging across mammals. We recently sequenced and analyzed the genomes of mammals differing in lifespan, described omics-based patterns that reflect their longevity and developed quantitative biomarkers to predict the biological age of species and the effects of longevity interventions. Our long-term goal is to employ these molecular tools to better explain aging and its drastically different rates across species, and ultimately develop better, unbiased approaches to extend human lifespan, healthspan and counteract ADRD. In the current phase of the PPG, we obtained exciting data that further support our general approach to lifespan control. We generated chromosome-level assemblies of the genomes of longest-lived rodents, described comprehensive molecular profiles across mammals, and developed quantitative biomarkers of aging for various mammals. We propose to benefit from these developments and, in close collaboration with Projects 1, 2 and 3 and Cores B and C, address critical questions in our understanding of natural differences in the aging rates and ADRD across mammals. (1) Development of species-specific and pan-mammalian biomarkers of aging. We will develop advanced tissue-specific and pan-tissue transcriptomic clocks for the mouse, rat, naked mole rat, and pan-rodent clocks; Alzheimer’s disease and ADRD-related aging clocks; epigenetic clocks based on long-range sequencing; and multi-omic clocks integrating the epigenome and transcriptome. (2) Comparative multi-omics of longevity at the basal life state. We will generate induced pluripotent stem cells for various species of mammals, carry out comparative cross-species analyses of these cells at the level of the transcriptome, metabolome, and epigenome, develop molecular signatures of longevity at the embryonic state; differentiate these cells to different lineages and develop cell type-specific longevity signatures; compare mammalian embryonic longevity signatures with the signatures of adult tissues. (3) Applications of multi-omics biomarkers to animal models of longevity and Alzheimer’s disease. We will apply biomarker tools to various animal models developed by this Program Project, testing the effects of interventions in mice based on our findings in long-lived species including epigenetic modifications, whale, beaver and human SIRT6 expression, whale CIRBP, cGAS-STING and PYHIN mutations in wild type and Alzheimer’s disease mice, and quantifying biological age and Alzheimer’s disease signatures in the brains of naked mole rat, degu, and nmrHAS2 and MSR-deficient mouse models.