Dampening the Power of the Brain—When Aging Meets Cognition

Aging dampens the power of the brain. While not all brain processes are equally affected, the detriments are serious and broad enough to adversely affect the quality of life for millions of people. From slower processing speed, to slackened recall, the effects of aging on the brain might make driving more dangerous or work more burdensome. Aging also leads to accumulating risk for even more insidious pathologies, such as sensitizing people to Alzheimer’s disease and related dementias. Just as the processes that integrate neural function variably decline with age, subsets of neural changes govern cognitive decline, such as reduced excitatory synaptic plasticity, increased neuroinflammation, and reduced regenerative capacity. The genetic and environmental factors driving the cellular changes that lead to cognitive decline are actively being investigated. In this issue of Journal of Gerontology Biological Sciences, 4 articles add to our understanding of the molecular and systemic determinants of normal brain aging, and an associated review presents therapeutic modalities that can potentially rejuvenate the aging brain and guard against neurodegenerative diseases.

Interplay Between Aging, Alzheimer’s Disease, and Cognitive Decline

The study of normative cognitive aging can be complicated by the overlap between factors that influence aging and Alzheimer’s disease. Thus, it is extremely important to examine the factors affecting both normal and diseased aging states, as well as the temporal dependencies of the aging process. In that regard, Legdeur et al measured markers of brain aging in a cross-sectional human cohort to find the determinants of cognitive decline (1). While they did not find a consistent pattern of changes in their markers, on average handgrip strength, hippocampal volume, and performance on the Digit Symbol Substitution Test (a measure of multiple cognitive functions) showed the most rapid decline, while the prevalence of abnormalities in amyloid aggregation and Mini-Mental State Examination (MMSE) scores (commonly used in dementia diagnosis) showed the slowest progression, suggesting that dementias afflict already sensitized aged brains. These results highlight the importance of developing cognitive reserve to counteract cognitive decline and thereby prevent further vulnerability to dementia-related neurodegenerative disease.

The longer we live, the more we become prone to diseases of aging—including Alzheimer’s disease—that could ultimately affect our longevity. As aging is regulated by genetic factors that may be distinct from those causing age-related disease, it is important to determine the shared and unique genetics of aging and disease. Thus, Kolicheski et al genotyped a neurologically healthy aging cohort of Caucasians for the candidate longevity gene CLEC3B, as well as the established longevity gene APOE (2). Previously, the tetranectin CLEC3B had been associated with extreme longevity in an Asian population (3). While the association with CLEC3B was not recapitulated in Caucasians, the authors did find the well-established APOE2 association with longevity. Interestingly, the frequency of APOE4 remained unchanged across their cohort, which is surprising because of its association with Alzheimer’s disease and anticorrelation with longevity (4).

Leveraging Animal Models to Interrogate Cognitive Decline

While human genome-wide association studies (GWAS) are the backbone of phenotypic gene discovery that influence human traits, animal models provide essential access to the underlying molecular mechanisms driving these phenotypes. Transcriptomics and proteomics of the aging human brain have identified decreased synaptic plasticity and increased neuroinflammation as the major changes associated with cognitive decline (5,6). Manipulation of genes that influence these processes in mice, such as transcription factors (7) and posttranslational modifiers that regulates synaptic plasticity (8), have confirmed the importance of these processes to cognitive aging across evolution. Orock et al further refine the model for the molecular changes that lead to age-related cognitive decline (9). They find that the levels of synaptobrevin-2 (SYB2), a SNARE protein that mediates synaptic vesicle neurotransmitter release, progressively decrease in the mouse hippocampus during aging starting at a relatively early age. Reducing levels of SYB2 in young mice recapitulates the cognitive deficits in spatial memory observed in aged mice. Interestingly, these cognitive deficits are reflected at the synaptic level by impaired maintenance of synaptic plasticity mediated by stunted synaptic vesicle release.

Counteracting Cognitive Decline

Discovery of the organismal, cellular, and molecular factors that influence brain aging are useful for developing interventions that slow cognitive decline and prevent dementia sensitization. Behavioral interventions, such as exercise and intermittent fasting, represent noninvasive interventions that can have profound rejuvenating effects on the aging brain. Exercise benefits cognitive function during aging, and these benefits are at least partially mediated by blood factor induction of neurotrophin signaling in the brain (10). Sanders et al investigated the interaction between exercise and allelic variants of neurotrophin genes on cognition in neurologically healthy participants in the Cache County Cohort (11). In this aged cohort, participants that exercised had a higher cognitive baseline, while exercise had relatively small effects on the rate of decline. single nucleotide polymorphisms (SNPs) in neurotrophin signaling genes that were previously linked to Alzheimer’s disease did not affect cognition in regards to exercise, other than relatively weak effects of 1 allele of NGFR in sedentary males. Exercise levels were self-reported in this study and adherence to exercise regimens over the course of the study unknown, making it difficult to determine the actual effects of exercise on participant cognition. The lack of effects of the different alleles of neurotrophin genes suggests that the levels of neurotrophin proteins induced by exercise might mask any effects of functional differences between alleles that only become apparent under already sensitized conditions.

The articles in this issue of Journal of Gerontology Biological Sciences leverage human data and animal models to highlight the importance of developing strategies to counteract brain aging with the hope of preventing age-related pathologies. To date, the combination of these approaches has revealed many of the molecular and cellular changes that lead to age-related cognitive decline. Early breakdown of the blood–brain barrier during aging sensitizes the brain to degeneration (12), and increasing diffusion across the blood–brain barrier leads to reduced cognition and loss of synaptic plasticity (13). These results suggest that systemic circulating factors mediate much of brain aging, which are confirmed by heterochronic parabiosis and plasma injection experiments (14). Importantly, systemic rejuvenating interventions also benefit the aged brain, suggesting that treatments need not be brain-specific. In that regard, the review by Wahl et al amasses evidence from the literature indicating that therapeutics that target the hallmarks of aging, even if they do not extend life span, have beneficial effects on the aging brain, and hold remarkable potential as treatments to reverse brain aging and counteract neurodegenerative diseases (15).

Funding

This work was supported by the National Institute on Aging (AG067740 and F32-AG050415)