Every cell in the human body undergoes a process of aging, similar to the organism. This cellular aging is a fundamental biological phenomenon that impacts various bodily functions over time. Understanding these changes provides insight into aging and its relationship to overall health. This process involves cells transitioning into a distinct state, differing from active division or cell death, influencing our health.
Understanding Senescent Cells
Aging cells, senescent cells, have permanently stopped dividing but remain metabolically active. This state differs from dead cells, which are cleared from the body, or old cells that still function normally and can divide. Senescent cells are characterized by a flattened and enlarged morphology, and molecular markers like telomere-dysfunction-induced foci, senescence-associated heterochromatin foci (SAHF), and increased senescence-associated β-galactosidase (SA-β-Gal) activity.
A defining feature of senescent cells is their resistance to programmed cell death (apoptosis). Instead of being removed, they persist in tissues and secrete the Senescence-Associated Secretory Phenotype (SASP). The SASP is a complex collection of pro-inflammatory cytokines, chemokines, growth factors, and proteases. This secreted cocktail influences the surrounding tissue environment.
Mechanisms of Cellular Aging
Cellular senescence can be triggered by several mechanisms. One prominent cause is telomere shortening, leading to replicative senescence. Telomeres are protective caps at the ends of chromosomes that shorten with each cell division. When telomeres reach a critically short length, they activate a DNA damage response, signaling the cell to enter irreversible growth arrest.
Another trigger for cellular aging is accumulated DNA damage, inducing stress-induced senescence. This damage can arise from sources like genotoxic stress, oxidative stress, or oncogenic signaling. Persistent DNA damage activates signaling pathways that enforce cell cycle arrest. Unrepaired DNA double-strand breaks are a common trigger.
Mitochondrial dysfunction also plays a role in cellular senescence. Mitochondria are the cell’s powerhouses, and their impaired function leads to decreased respiratory capacity and increased reactive oxygen species (ROS) production. This increased ROS can cause DNA damage, further contributing to senescence. Mitochondrial dysfunction is both a cause and a consequence of cellular senescence, forming a feedback loop sustaining the senescent state.
Cellular Aging and Health
The accumulation of senescent cells has widespread implications for health, due to their persistent presence and the molecules they secrete. These cells, even when making up a small percentage of tissue, contribute to chronic, low-grade inflammation, sometimes called “inflammaging.” The Senescence-Associated Secretory Phenotype (SASP) drives this inflammation, releasing pro-inflammatory cytokines, chemokines, and matrix metalloproteinases into the surrounding tissue.
This chronic inflammatory environment disrupts normal tissue function and impairs organ regeneration. Senescent cells can occupy cellular niches, leading to tissue dysfunction and impaired stem cell function. Their accumulation and SASP have been linked to the development of various age-related conditions.
These conditions include cardiovascular diseases like atherosclerosis and heart failure, neurodegenerative disorders such as Alzheimer’s disease, and metabolic diseases like type 2 diabetes. Senescent cells contribute to these pathologies by promoting oxidative stress, remodeling the extracellular matrix, and disrupting cellular energy metabolism, which can lead to insulin resistance. They are also associated with muscle weakness, frailty, and a weakened immune system, increasing susceptibility to infections and illnesses with age.
Current Research on Aging Cells
Current research actively explores ways to understand and potentially manipulate senescent cells to improve health. Researchers are investigating compounds known as “senolytics,” which are designed to selectively eliminate senescent cells. Preclinical studies in mice have shown that removing these cells can improve tissue function, delay age-related diseases, and extend lifespan. For example, dasatinib and quercetin have reduced senescent cell burden in human adipose tissue in a pilot study.
Another area of research focuses on “senomorphics” (also called senostatics), compounds that suppress the harmful secretions of senescent cells, especially the SASP, without killing the cells. The goal of senomorphic therapies is to mitigate the pro-inflammatory and tissue-damaging effects of SASP, effectively “quieting” senescent cells. Examples include rapamycin and metformin, which can inhibit SASP production through pathways like mTOR and NF-κB.
The broader objective of this research is to enhance “healthspan,” which refers to the period of life spent in good health, and to address age-related diseases. Ongoing clinical trials are evaluating the safety and effectiveness of these senescence-targeting agents in humans across various conditions, including idiopathic pulmonary fibrosis, diabetic kidney disease, and osteoarthritis. These studies aim to translate promising preclinical findings into benefits for human health, with efforts also focused on identifying new biomarkers to track senolytic efficacy.