Aging entails a gradual decline in physiological function, making the body more susceptible to dysfunction and mortality. This process is a key contributor to various diseases like cancer, diabetes, cardiovascular issues, and neurodegenerative disorders. Recent advancements in aging research have unveiled genetic pathways and biochemical mechanisms that influence the rate of aging, a discovery with profound implications. This article outlines nine fundamental hallmarks of aging, observed across different organisms, with a focus on mammalian aging. These hallmarks include genomic instability, telomere shortening, epigenetic changes, impaired protein regulation, disrupted nutrient sensing, mitochondrial dysfunction, cellular senescence, diminished stem cell activity, and altered cell communication. Understanding the interconnectedness of these hallmarks and their roles in aging is critical for identifying potential pharmaceutical targets to enhance human health during aging, while minimizing adverse effects.
Introduction
The concept of aging, defined as the progressive decline in function over time affecting most living organisms, has captured human curiosity and imagination for centuries. However, it wasn't until the isolation of the first long-lived strains in Caenorhabditis elegans (C. elegans) in 1983 that aging research entered a new era. Today, aging is under intense scientific investigation, driven by our expanding understanding of the molecular and cellular mechanisms underlying life and disease. Interestingly, the current state of aging research bears resemblance to the trajectory of cancer research in past decades. The landmark paper by Hanahan and Weinberg in 2000, outlining the six hallmarks of cancer, marked a turning point in cancer research and has since been expanded to ten. This classification has helped in conceptualizing the essence of cancer and its underlying mechanisms.
Although cancer and aging may appear as opposite processes at first glance, they share common origins. Both are rooted in the time-dependent accumulation of cellular damage, which is widely regarded as the fundamental cause of aging. This damage can occasionally confer aberrant advantages to certain cells, leading to cancer. Thus, cancer and aging can be viewed as different manifestations of the same underlying process—the accrual of cellular damage. Moreover, many age-related pathologies, such as atherosclerosis and inflammation, involve uncontrolled cellular growth or hyperactivity.
In light of this conceptual framework, the field of aging research is focused on understanding the sources of aging-related damage, the compensatory responses that attempt to restore balance, the interconnectedness between different types of damage and compensatory responses, and the potential for interventions to delay aging. To this end, we have endeavored to identify and categorize the cellular and molecular hallmarks of aging. We propose nine candidate hallmarks that contribute to the aging process and collectively define the aging phenotype. While our focus is primarily on mammalian aging, insights from simpler model organisms have also been considered. Each hallmark ideally meets specific criteria: it should manifest during normal aging, experimental exacerbation should accelerate aging, and experimental amelioration should delay the aging process and increase healthy lifespan. However, achieving this last criterion is challenging, as interventions targeting one aspect of aging may impact others due to the extensive interconnectedness between aging hallmarks.
The scheme enumerates the nine hallmarks described in this Article: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication.