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GENERAL PRINCIPLES

The past 30 years have produced a revolution in the scientific understanding of the biologic processes that underlie aging. The mechanisms of aging can be elucidated, categorized, measured, manipulated in the laboratory, and, now, targeted in clinical trials to improve the health of older adults. Why consider aging itself as a therapeutic target? Simply put, aging as a risk factor for disease and disability dwarfs all others on a population level. For a litany of chronic, “age-related diseases,” including heart disease, cancer, type 2 diabetes mellitus, and Alzheimer disease, age is by far the dominant risk factor, and with each decade of life over 50 years, the risk increases exponentially. Moreover, the impact of any specific disease pathophysiology is projected through the lens of aging. A broken bone is a temporary inconvenience for a young adult, but a life-changing and often fatal event for a frail older adult. Loss of independence and geriatric syndromes, such as falls, immobility, frailty, and incontinence, are rarely due to a single disease process but rather to the accumulation of physiologic dysfunctions in multiple systems for which biologic aging is the common underlying factor. Treating or preventing any one individual disease without addressing aging can often have only a limited impact, because one disease or problem will be exchanged for another. The practice of geriatric medicine targets aging at a clinical level; now the complementary field of geroscience is emerging to target aging at a biologic level.

The geroscience hypothesis posits that interventions targeting the biology of aging might prevent or delay a wide range of age-related diseases or conditions simultaneously and thus have an outsized effect on preventing disability, dependence, and death. The geroscience hypothesis is currently being tested in clinical trials. These geroscience-informed clinical trials have driven rapid advances in trial design, interventions, and biomarker development, but the underlying science has also spurred the development of unregulated and often harmful pseudomedicine. In this chapter, we will provide a concise overview of the current state of understanding of the biologic mechanisms of aging, a summary of clinical trials testing geroscience interventions, an overview of candidate biomarkers of aging, and practical suggestions for advising patients about purported aging therapies in this emerging field.

BIOLOGIC CAUSES OF HUMAN AGING

Central to the geroscience hypothesis is an emerging understanding of the biological causes of human aging. Years of exploration into how human cells and organs function led to the discovery of a set of unifying mechanisms that explain the aging process, known as hallmarks or pillars of aging (Figure 23–1). These aging mechanisms include:

  • Genomic instability and buildup of DNA damage

  • Epigenetic alterations, or changes in how genes are turned on or expressed

  • Proteostasis and the accumulation of damaged and misfolded proteins

  • Changes in pathways that regulate growth, metabolism, and nutrient sensing

  • Loss of adult stem cells and ability of cells ...

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