TY - JOUR
T1 - Biological aging processes underlying cognitive decline and neurodegenerative disease
AU - Gonzales, Mitzi M.
AU - Garbarino, Valentina R.
AU - Pollet, Erin
AU - Palavicini, Juan P.
AU - Kellogg, Dean L.
AU - Kraig, Ellen
AU - Orr, Miranda E.
N1 - Funding Information:
This work was made possible by grants through the Alzheimer’s Drug Discovery Foundation (GC-201908-2019443); the Alzheimer’s Association Part the Cloud + Bill Gates Partnership (PTCG-20-695184); the National Institute on Aging (R21AG068731, P30AG066546); the Institute for Integration of Medicine & Science and the Center for Biomedical Neurosciences at the University of Texas Health Science Center at San Antonio; and the Coordinating Center for Claude D. Pepper Older Americans Independence Centers (U24AG059624). VRG is supported by an NIH Clinical and Translational Science Award (TL1 TR0026). MMG has received funding from the Texas Alzheimer’s Research and Care Consortium, the National Institute on Aging, the San Antonio Claude D. Pepper Older Americans Independence Center, the Alzheimer’s Association Part the Cloud + Bill Gates Partnership, and the Alzheimer’s Drug Discovery Foundation. VRG has received funding from the National Institute on Aging. JPP has received funding from the National Institute on Aging and the San Antonio Claude D. Pepper Older Americans Independence Center. MEO has received funding from the Alzheimer’s Drug Discovery Foundation, the Cure Alzheimer’s Fund, the Charleston Conference on Alzheimer’s Disease, the Older Americans Independence Center National Coordinating Center, the National Institute on Aging, the National Institute of Neurological Disorders and Stroke, the North Carolina Diabetes Research Center, and the US Department of Veterans Affairs.
Publisher Copyright:
© 2022, Gonzales et al.
PY - 2022/5/16
Y1 - 2022/5/16
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85130023417&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85130023417&partnerID=8YFLogxK
U2 - 10.1172/JCI158453
DO - 10.1172/JCI158453
M3 - Review article
C2 - 35575089
AN - SCOPUS:85130023417
SN - 0021-9738
VL - 132
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 10
M1 - e158453
ER -