Edit Agenda item: Hallmarks of Biological Failure/Metabolic Integrity & Aging: Amplification of Small Perturbations

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Abstract	Caloric restriction (CR) delays aging and the onset of age-related disease in diverse species, including nonhuman primates. Emerging data has focused our studies on links between metabolic status and disease vulnerability; several diseases of aging including diabetes, cancer, and neurodegeneration, have an established metabolic component. Candidate factors involved in longevity regulation are nutrient sensitive and interconnected in terms of signaling pathways and downstream effector actions. Molecular profiling of the transcriptome, proteome, and metabolome identifies CR responsive elements that are highly enriched for metabolic pathways. Here too connectivity among responsive nodes, or mega clusters, is complex. Our recent work shows that small changes in metabolic status precipitate large-scale multi-modal functional changes across diverse cellular processes. We suggest that modest failures in metabolic integrity are amplified by such mechanisms with age to broadly impact homeostasis and adaptation, creating shared vulnerability to diseases and conditions despite differences in their etiology.

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