Aging
Series edited by James L. Kirkland
Reviews tackle aging across a wide range of disciplines.
Articles in series
Abstract
The mechanisms that explain mitochondrial dysfunction in aging and healthspan continue to be studied, but one element has been unexplored: microproteins. Small open reading frames in circular mitochondria DNA can encode multiple microproteins, called mitochondria-derived peptides (MDPs). Currently, eight MDPs have been published: humanin, MOTS-c, and SHLPs 1–6. This Review describes recent advances in microprotein discovery with a focus on MDPs. It discusses what is currently known about MDPs in aging and how this new understanding could add to the way we understand age-related diseases including type 2 diabetes, cancer, and neurodegenerative diseases at the genomic, proteomic, and drug-development levels.
Authors
Brendan Miller, Su-Jeong Kim, Hiroshi Kumagai, Kelvin Yen, Pinchas Cohen
Abstract
Alzheimer’s disease and related dementias (ADRD) are among the top contributors to disability and mortality in later life. As with many chronic conditions, aging is the single most influential factor in the development of ADRD. Even among older adults who remain free of dementia throughout their lives, cognitive decline and neurodegenerative changes are appreciable with advancing age, suggesting shared pathophysiological mechanisms. In this Review, we provide an overview of changes in cognition, brain morphology, and neuropathological protein accumulation across the lifespan in humans, with complementary and mechanistic evidence from animal models. Next, we highlight selected aging processes that are differentially regulated in neurodegenerative disease, including aberrant autophagy, mitochondrial dysfunction, cellular senescence, epigenetic changes, cerebrovascular dysfunction, inflammation, and lipid dysregulation. We summarize research across clinical and translational studies to link biological aging processes to underlying ADRD pathogenesis. Targeting fundamental processes underlying biological aging may represent a yet relatively unexplored avenue to attenuate both age-related cognitive decline and ADRD. Collaboration across the fields of geroscience and neuroscience, coupled with the development of new translational animal models that more closely align with human disease processes, is necessary to advance novel therapeutic discovery in this realm.
Authors
Mitzi M. Gonzales, Valentina R. Garbarino, Erin Pollet, Juan P. Palavicini, Dean L. Kellogg Jr., Ellen Kraig, Miranda E. Orr
Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)