Summary: Removing senescent cells may help reverse some signs of aging, researchers report.
Source: Cell Press
Removing senescent cells — those with a persistent damage response that accumulate with age — has shown striking benefits in animal studies. Elderly mice can regrow fur, run faster, and recover organ function after senescent-cell clearance. While these findings are promising, Peter de Keizer of Erasmus University Medical Center cautions against premature hype. In an Opinion published December 29 in Trends in Molecular Medicine, he outlines the remaining scientific and safety milestones needed before human translation can be realistically considered.
Cellular senescence was first described in the 1960s and has re-emerged in recent years as a target for therapies that aim to slow or reverse aspects of aging. Senescent cells not only stop dividing; many adopt a secretory phenotype that releases pro-inflammatory and tissue-degrading factors. These secreted factors can disrupt local tissue function and negatively affect neighboring cells.
To explain one way this disruption may occur, de Keizer proposes a “senescence–stem lock” model: chronic secretion from senescent cells may lock surrounding cells into an inappropriate stem-like or dedifferentiated state, which in turn prevents proper differentiation and tissue renewal. If true, simply removing senescent cells might not be enough; therapies may also need to promote the correct reawakening and differentiation of nearby stem or progenitor cells to restore healthy tissue structure and function.
“When you take a damaged car into the shop, removing rust and broken parts is not enough — you also want to replace missing or worn components,” says de Keizer. “An ideal anti-senescence therapy would both clear harmful senescent cells and stimulate regeneration by encouraging appropriate differentiation of local stem cells. This approach could complement other rejuvenation strategies, such as transient expression of stem-cell factors.”
Important basic research questions remain. Identifying potential safety issues and off-target effects is critical and currently understudied even in animal models. Senescent cells can have beneficial, time-limited roles in processes like wound healing, so indiscriminate removal at the wrong time could be harmful.
De Keizer highlights three major milestones needed before anti-senescence approaches can be considered for human use:
- Milestone #1: Proof of Concept
Multiple studies have tested whether senescence contributes causally to aging. In mice, removing senescent cells extended lifespan and delayed age-related decline in some tissues, providing experimental evidence that targeting senescence can influence organismal aging. - Milestone #2: Safe Therapeutics
Early anti-senescence compounds have been reported, including combinations like quercetin with dasatinib and agents targeting BCL-family proteins. Many of these first-generation compounds lack perfect selectivity and can affect non-senescent cells, so further optimization and rigorous safety testing are necessary before clinical use. - Milestone #3: Reversal of Aging
Beyond slowing deterioration, the field must determine whether senescent-cell clearance can reverse established, age-related damage. While halting or delaying aging features is increasingly plausible, whether some age-related diseases can be fully reversed remains an open question.
“Even if we develop an excellent anti-senescence treatment, the next challenge is to combine it with strategies that actively rejuvenate tissue,” says de Keizer. “We should resist overstating early results about new compounds and focus on careful, evidence-based development. Still, the progress to date is exciting, and I am optimistic that applicable anti-senescence therapies that reduce age-related pathology will be found.”
Researchers must also clarify optimal timing and target populations for anti-senescence therapies — for example, whether interventions should be preventive, administered at early signs of dysfunction, or used to treat established disease. Practical considerations such as cost, accessibility, and possible off-target toxicities will affect how widely such therapies can be adopted if they prove effective.
De Keizer plans to co-found a company to develop anti-senescence compounds discovered in his laboratory. He suggests that highly specific agents, such as cell-penetrating peptides that block selected activities of senescent cells, may offer advantages over broad-spectrum inhibitors by reducing unintended effects on healthy cells.
Funding: This work was supported by Erasmus University Medical Center and the Dutch Cancer Society.
Source: Vanessa McMains — Cell Press
Image source: Illustration for context; The Fountain of Youth, Lucas Cranach the Elder, circa 1546.
Original research: Opinion article “The Fountain of Youth by Targeting Senescent Cells?” by Peter L. J. de Keizer, Trends in Molecular Medicine. Published online December 2016. doi:10.1016/j.molmed.2016.11.006
Cell Press. “Anti-Aging Therapies Targeting Senescent Cells: Facts and Fiction.” NeuroscienceNews. Published December 30, 2016.
Abstract
The Fountain of Youth by Targeting Senescent Cells?
Reversing or slowing aging has long captured scientific and public imagination. Recent attention has focused on cellular senescence as a contributor to aging and age-related disease. Key questions include whether senescent cells can be safely and effectively eliminated, when interventions should be applied, and whether targeting senescence alone is sufficient to restore tissue health. Advances in tools to study senescence now permit more rigorous testing of these questions. It will be important to understand how senescence impairs tissue regeneration and to design therapeutics that both neutralize harmful senescent-cell signals and promote safe rejuvenation. The author argues that cell-penetrating peptides and selective modulation of pathways such as FOXO signaling may be promising directions for future therapy development.
Trends summarized:
– Experimental removal of senescent cells can delay age-related decline in mice, supporting a causal role for senescence in aging.
– Initial screens have identified candidate anti-senescence compounds, but many current agents lack ideal selectivity or have toxicity concerns.
– Cell-penetrating peptides offer a route to precisely disrupt pathogenic protein–protein interactions in senescent cells and have shown promise in other clinical contexts.
– Senescent cells impair tissue environments through direct contact and by secreting SASP factors, which may lock neighboring cells into dysfunctional states and reduce regenerative capacity.
– Targeting specific regulatory pathways, including select FOXO-related mechanisms that influence p21Cip1 and stemness regulators, could counteract senescence while promoting rejuvenation.
“The Fountain of Youth by Targeting Senescent Cells?” by Peter L. J. de Keizer. Trends in Molecular Medicine. Published online December 2016. doi:10.1016/j.molmed.2016.11.006