Hayflick’s Lament Revisited

Many of us desire to live longer, but we also want to remain healthy and be physically and mentally strong. Diet, exercise, and lifestyle can contribute to health and longevity, but there is a limit to what even the healthiest of choices can do to stop the biological deterioration of our bodies over time. In 1965, Leonard Hayflick published his observations that cells could only undergo a fixed number of cell divisions, roughly 50 times, before they grew old and entered a nondividing state known as senescence. This concept that cells have an inherent biological clock that inevitably winds down to senescence and death became known as Hayflick’s lament. While sentencing cells to senescence and death may at first seem like a harsh evolutionary outcome, subsequent work showed that senescence has significant biological roles. Senescence occurs in waves during embryological developments and appears to be critical for normal differentiation of cells into our various tissues. Additionally, at the end of pregnancy, the programmed senescence of placental membranes may act as the trigger to initiate labor. However, the role of senescence doesn’t stop at birth as senescence seems to be involved in tissue repair after injuries and is very important in cancer prevention. Cancer is a two-step process. First, normal cells acquire genetic damage during our lifetimes that transforms them into rogue cells that grow uncontrollably. However, these transformed cells will still eventually senesce and die so they won’t accumulate indefinitely to form a cancerous tumor. To become cancerous, the transformed cells also need a second step where they acquire additional genetic changes that allow them to bypass senescence and become immortal. The current thinking is that cellular senescence evolved as a defense mechanism that makes it harder for cancers to form.

Work over the last two decades has shown that while senescence makes positive contributions to our biology, it also directly promotes the physical decline of aging. Senescent cells secrete inflammatory proteins that can damage surrounding cells and induce their early senescence so that senescent cells build up in the tissue. Simply implanting senescent cells into young mice reduces their physical fitness and increases their risk of early death. Conversely, giving older mice drugs that killed senescent cells rejuvenated their physical capabilities and slightly extended their lives compared to control mice. Other studies used genetic tricks in mice to remove senescent cells, and these studies showed reduced atherosclerotic plaques, improvement in cartilage and bone strength, and decreased neurogenerative symptoms in an Alzheimer’s model. These and other results suggested that careful targeting of human senescent cells could improve health and fitness in the elderly even if there is no significant life extension.

Several research groups and companies are currently working on developing “senolytic” drugs to kill senescent cells in humans. While the wholesale killing of senescent cells could cause problems, for example by impairing wound healing, targeted application for specific diseases seems feasible. Phase 1 clinical trials are underway for at least two diseases: diabetes-related kidney fibrosis and osteoarthritis. Early results published for the kidney study showed that patients receiving the test drug combination had reduced numbers of senescent cells with no significant adverse effects, an encouraging first step. The FDA has approved a phase 2 study to look at the actual efficacy of the drugs in patients with the disease, so more information should be available by next year. It’s way too early to know if senolytics will ever translate from the research lab into actual therapeutics, but it’s an exciting and promising concept that could have great benefits if researchers figure out how to harness it effectively.

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