Exercise and Epigenetics in Neurodegeneration

It is indisputably the case that regular exercise and maintenance of physical fitness into later life lowers the incidence and slows the progression of neurodegenerative disease. One can write any number of reviews akin to today's open access paper, walking through the evidence for cellular pathways involved in neurodegeneration to be beneficially influenced by physical activity, as well as the epidemiological data linking fitness and exercise with a reduced burden of neurodegeneration in the broader population. There is a great deal of evidence, even even we restrict ourselves to only those studies published in the past twenty years or so.

The focus in today's paper is the effects of exercise on epigenetic regulation via DNA methylation. The nuclear genome is methylated at numerous distinct CpG sites, an ever-changing pattern of decorations that shift the structure of the genome in ways that enable or disable expression of specific genes. DNA methylation status is maintained by a complex array of machinery and feedback loops that react to the circumstances a cell finds itself in. Since aging occurs for the same underlying reasons in all of us, the pattern of methylation status changes in characteristic ways with age. This has allowed the production of epigenetic clocks to measure the burden of biological aging, constructed via machine learning approaches.

It is interesting to note that, as the authors of this paper point out, there are any number of specific instances one can point to in which physical activity has been shown to alter DNA methylation machinery in ways that affect neurodegenerative processes. Further, physical activity and fitness clearly reduces mortality and disease incidence, a modest slowing of aging. Yet the original Horvath epigenetic clock is insensitive to differences in physical fitness, despite performing well in many other circumstances. Later clocks such as GrimAge appear to be better in this regard, but it is certainly a concern.

This highlights the major issue with epigenetic clocks, as well as related measures of aging produced from other biological data. Given that they were produced by mining omics data in search of patterns, it is unclear as to what exactly they measure. Aging consists of numerous interacting processes, proceeding largely in parallel in any given individual. Any given clock implementation may well reflect the consequences of only some of those processes, and thus may be a bad choice if used to assess the results of any given approach to treating aging as a medical condition. The only sure way to calibrate a clock in order to validate its use for a specific scenario is the hard way: run a life span study.

Roles of physical exercise in neurodegeneration: reversal of epigenetic clock

The lack of physical exercise (PE) is a common phenomenon in modern society and has become a risk factor for many diseases, including cardiovascular diseases, metabolic dysfunctions, cancers, and neurodegenerative diseases. Appropriate exercise shapes the athletic figure and improves the body's basal metabolic rate. PE also plays a vital role in brain health, especially in preventing and alleviating the decline of cognitive function as well as the occurrence of some neurodegenerative diseases. The positive effects of regular, long-term physical activities and exercise interventions on cognition have been reported in the literature. Since only limited therapies are available for cognitive impairment, exercise may serve as a promising non-pharmaceutical treatment.

The process of brain aging, which is one of the risk factors for neurodegeneration, has been found to involve epigenetic mechanisms. Epigenetics, by definition, refers to a set of heritable mechanisms and phenomena that determine cell phenotypes without changing the genome. Epigenetic modifications such as abnormal DNA methylation (DNAm), microRNAs, and histone modifications are closely associated with damage to brain health and neurodegenerative diseases. As individuals age, the age-related changes are often linked to the fluctuating methylation levels of specific genes.

The DNAm has been proposed as a potential multi-tissue estimator of biological age and the concept of epigenetic clock (i.e., DNAm clock) has been developed with a suitable regression model to systemically measure the biological age. This tool has been extensively applied to distinguish between chronological age and biological age, as well as to estimate the corresponding health/disease status. While healthy individuals have almost identical chronological age and biological age (normal aging), patients with cancer and neurodegenerative diseases are biologically older (pathologic aging) and the offspring of centenarians are biologically younger (delayed aging). Therefore, the epigenetic clock is capable of assessing the state of aging among populations. Moreover, DNAm is associated with environmental and lifestyle factors, which have the capacity for regulating epigenetic variability in the brain. Given the effects of such factors as PE in slowing down the epigenetic age acceleration or even resetting the aging clock, the epigenetic clock has progressively become an exciting area of research.

In this review, we summarize brain-specific, disease-related mechanisms involving DNAm, through which PE reverses epigenetic changes to ameliorate neurodegeneration in aging, AD, and PD. We also integrate data from muscular-related molecule cascades in the periphery, which are directly induced by PE to affect the central nervous system (CNS). Furthermore, as a potential mediator of motor skills, DNAm can be modulated to improve the pathological symptoms of dyskinesia-related neurodegenerative diseases. The role of PE in neurodegeneration is further explored from the perspective of epigenetic-related mechanisms, and PE can be viewed as a potential rejuvenation therapy.

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