Cellular senescence represents a biological process linked to the body’s aging trajectory. Discovered in the early 1960s, it describes a state where cells permanently stop dividing. Research into cellular senescence offers insights into mechanisms governing cellular health and age-related changes.
Understanding Cellular Senescence
Cellular senescence is a state where cells cease to divide but remain metabolically active, distinguishing them from quiescent or terminally differentiated cells. This permanent growth arrest is often triggered by cellular damage or stress, such as telomere shortening, DNA damage, or oncogenic signals. For instance, as cells replicate, their telomeres progressively shorten, eventually halting further division.
Senescent cells exhibit several distinct characteristics, including an enlarged and flattened morphology, altered gene expression, and resistance to programmed cell death. A hallmark feature is the development of a Senescence-Associated Secretory Phenotype (SASP). The SASP involves the secretion of pro-inflammatory cytokines, chemokines, growth factors, and proteases, which can alter the surrounding tissue environment.
Cellular Senescence and the Aging Process
The accumulation of senescent cells contributes to aging. As these cells persist in tissues with age, their secreted SASP factors drive chronic low-level inflammation, often termed “inflammaging.” This sustained inflammatory state can disrupt tissue homeostasis, impairing the function of neighboring healthy cells and leading to a decline in organ function. The SASP also contributes to the degradation of the extracellular matrix and can affect stem cell function, compromising tissue repair and regeneration.
Senescent cells are implicated in the development and progression of numerous age-related conditions. Their presence has been linked to diseases such as osteoarthritis, where they contribute to joint degradation, and atherosclerosis, affecting vascular health. Neurodegenerative diseases, including Alzheimer’s, and conditions like sarcopenia, characterized by muscle loss, also show connections to senescent cell accumulation and their pro-inflammatory secretions.
The Double-Edged Nature of Senescent Cells
Cellular senescence has both protective and detrimental roles. In beneficial contexts, senescence acts as a barrier against cancer by preventing the proliferation of damaged or potentially cancerous cells.
They also play a part in embryonic development and wound healing. During wound repair, the temporary presence of senescent cells and their SASP can promote tissue regeneration and remodeling, aiding in the healing process. However, when these cells persist and accumulate beyond their temporary beneficial roles, their chronic pro-inflammatory SASP can become detrimental, contributing to chronic inflammation, tissue dysfunction, and the onset of age-related diseases. The impact of senescent cells depends on their context, duration of presence, and overall burden within tissues.
Emerging Strategies to Target Senescence
Research explores therapeutic approaches to modulate or eliminate senescent cells, countering aging and age-related diseases. These strategies fall into two categories: senolytics and senomorphics. Senolytics are compounds designed to selectively induce programmed cell death in senescent cells, thereby clearing them from tissues.
Examples of senolytics under investigation include the combination of dasatinib and quercetin, which target pathways like PI3K/AKT to trigger apoptosis in senescent cells. Fisetin, a natural flavonoid, and navitoclax, an inhibitor of the BCL-2 family of anti-apoptotic proteins, are also being studied for their senolytic properties. Senomorphics, in contrast, do not kill senescent cells but instead alter their phenotype, specifically by reducing or inhibiting the harmful effects of the SASP. These compounds aim to suppress the pro-inflammatory secretions by targeting signaling pathways such as mitogen-activated protein kinases (MAPKs), nuclear factor-kappa B (NF-κB), mTOR, and IL-1α.