Ageing is an inevitable process, but science continues to uncover ways to slow it down. One key area of research focuses on cellular senescence, where cells stop dividing but remain active. While senescence helps prevent cancer, its accumulation contributes to tissue dysfunction and chronic diseases. Researchers have been exploring ways to eliminate these aged cells using senolytic compounds, which selectively target and remove them.
A recent study examined whether these drugs could reduce biological ageing in human blood samples. By analysing age-related markers, particularly epigenetic age predictions, scientists aimed to determine if a short-term senolytic treatment could lead to measurable rejuvenation. The findings revealed that specific compounds reduced epigenetic age, hinting at the potential of senolytics in age-related therapies.
Link Between Senescence and Ageing
Cells enter senescence when they experience significant stress or DNA damage. Instead of dividing, they remain in a dormant state, producing inflammatory signals that can harm surrounding tissues. This process was initially thought to be beneficial, as it prevents damaged cells from becoming cancerous. However, over time, these senescent cells accumulate, contributing to ageing and age-related diseases.
Epigenetic changes play a crucial role in this process. DNA methylation, a chemical modification of DNA, shifts in predictable ways as people age. By analysing these patterns, scientists can estimate biological age, which may differ from chronological age. The study investigated whether eliminating senescent cells through senolytic drugs would also reverse these epigenetic markers, potentially reducing biological age.
Testing Senolytic Compounds in Blood Samples
To explore this possibility, researchers treated human blood samples with eight different senolytic compounds for three days. These compounds were chosen based on their ability to disrupt key survival pathways in senescent cells. The goal was to observe whether any of these drugs could lower epigenetic age predictions, which serve as an estimate of biological ageing.
The study analysed blood samples from donors between 22 and 68 years old. Scientists measured DNA methylation at specific sites associated with ageing and compared the results before and after treatment. If the drugs effectively eliminated senescent cells, researchers expected a reduction in epigenetic age.
Promising Findings in Age Reduction
After treatment, four compounds stood out for their ability to lower epigenetic age predictions. These compounds were RG7112, JQ1, AMG232, and Nutlin-3a. Each of these drugs influenced age estimates differently, but all showed a significant reduction in biological age. RG7112 had the strongest effect, reducing epigenetic age by up to 3.9 years. JQ1 and AMG232 lowered age predictions by approximately 3.0 years. Nutlin-3a also showed a decline, though the results were not statistically conclusive.
The remaining four compounds did not demonstrate a clear effect on epigenetic ageing. This suggests that not all senolytics work in the same way, and their effectiveness may depend on the type of cells they target.
How These Compounds Work
Each of the successful compounds disrupts pathways that allow senescent cells to survive. RG7112, AMG232, and Nutlin-3a inhibit the interaction between p53 and MDM2, leading to apoptosis, or programmed cell death. This mechanism ensures that damaged cells are removed rather than lingering in tissues. JQ1 works differently by interfering with a DNA repair pathway, making it easier for senescent cells to be eliminated.
These findings indicate that targeting senescent cells through specific pathways can have a rejuvenating effect. By selectively removing these cells, the biological age of blood samples decreased, suggesting that similar interventions could work in living organisms.
Measuring Other Signs of Ageing
To further validate the impact of these treatments, researchers also examined other markers of cellular ageing. One key test measured senescence-associated beta-galactosidase (SA-β-gal), a common indicator of senescence. The number of SA-β-gal-positive cells decreased significantly in samples treated with RG7112, JQ1, and Nutlin-3a. This confirmed that these drugs actively removed senescent cells rather than simply altering epigenetic markers.
Another observation involved changes in immune cell composition. Treatment with senolytics affected the balance of different blood cells, particularly by reducing larger, irregularly shaped cells. These shifts suggest that senolytic drugs influence not just ageing markers but also the overall cellular environment.
Challenges of Measuring Biological Age
Despite these promising results, the study acknowledges that epigenetic ageing and cellular senescence are not identical processes. While the tested compounds lowered epigenetic age, researchers could not confirm whether this directly resulted from eliminating senescent cells. Some scientists argue that DNA methylation changes occur independently of cellular senescence, meaning the observed effects may not be solely due to the removal of aged cells.
Additionally, the methods used to detect senescent cells have limitations. The SA-β-gal test, for example, does not exclusively measure senescence. Some non-senescent cells also show positive results, which could lead to misleading conclusions. Because of these challenges, future studies need to refine how senescence and ageing are measured to better understand the effects of senolytic compounds.
The Need for Further Research
While this study provides strong evidence that senolytic compounds can reduce biological age in vitro, further research is necessary. The findings were based on short-term treatment in isolated blood samples. Scientists must determine whether these effects hold true in living organisms over longer periods.
Additionally, the long-term safety of senolytic drugs remains uncertain. While they selectively target senescent cells, they may also impact other cellular processes. Before these compounds can be considered for human anti-ageing therapies, clinical trials must assess their safety and effectiveness in reducing age-related diseases.
Future of Senolytic Therapy
The idea of reversing biological age is no longer just a fantasy. Senolytic compounds have shown their potential to eliminate harmful aged cells and rejuvenate tissues. If ongoing research confirms their benefits, these drugs could become a valuable tool in the fight against ageing and age-related diseases.
While many questions remain, the study's findings mark an important step toward understanding how targeted interventions can influence ageing at the cellular level. With continued exploration, senolytic compounds could one day play a key role in extending healthspan and improving quality of life.
The study is published in the journal Npj Aging. It was led by Wolfgang Wagner and team from RWTH Aachen University Medical School.
