In today's open access paper, researchers review what is known of the ways in which the hallmarks of aging are involved in the aging of the brain, from initial cognitive decline through to later dementia. Interestingly, chronic inflammation is increasingly implicated in brain aging and the onset of dementia, and many of the hallmarks can be connected to inflammation. This is a direct connection in some cases, such as the presence of senescent cells that generate an outsized amount of pro-inflammatory signaling in comparison to their numbers. Other issues produce inflammation more indirectly, such as the numerous impairments in cell function, including disarray in mitochondrial function, autophagy, and epigenetic patterns, that lead to failure of the blood-brain barrier. That barrier leaks, leading to inflammation as inappropriate molecules and cells make their way into the brain.
Epigenetic aging is an increasingly interesting topic, given the prospect of epigenetic rejuvenation via partial reprogramming. Epigenetic changes that occur with aging are perhaps caused by cycles of DNA damage and repair, causing a depletion of factors needed to maintain youthful epigenetics. Reprogramming causes a reset in epigenetic marks, and resulting benefits in cell function. To what degree do age-related epigenetic changes result in inflammatory behavior in addition to other dysfunctions in cell behavior? That is an interesting question that has yet to be usefully answered. As noted above, the consequence of inflammation many not be a direct outcome of changed cell behavior, and rather lie at the end of a chain of downstream items. The best way to find out is for the research community to continue to apply reprogramming therapies in animal studies and observe the outcomes.
Alzheimer's disease and related dementias (ADRD) are among the top contributors to disability and mortality in later life. After the age of 65, the incidence of ADRD nearly doubles every 5 years, and by the ninth decade of life, approximately one of every three adults meets criteria for dementia. 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.
Biological pathways underlying normal cognitive aging and ADRD are likely to overlap, existing along a continuum. Targeting fundamental processes underlying biological aging may represent a yet relatively unexplored avenue to attenuate both age-related cognitive decline and ADRD. The biology-of-aging field has made substantial gains in identifying the pathophysiological processes that contribute to biological aging and multisystem organ decline.
In a seminal paper, researchers defined nine hallmarks of aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, dysregulated nutrient sensing, mitochondrial dysfunction, stem cell exhaustion, altered intercellular communication, and cellular senescence. These aging hallmarks and others have been implicated as pathogenic factors underlying numerous chronic age-related diseases, including ADRD. In animal models, targeting biological aging processes has extended both lifespan and healthspan, suggesting the possibility that these approaches may have beneficial effects for cognitive health as well.