As recently as the mid-20th century, ageing was described by Nobel Prize laureate Peter Medawar as “an unsolved problem in biology”. Today, researchers can analyse the activity of thousands of genes in individual cells and identify genetic variants linked to longevity. These studies identify molecular pathways that influence lifespan, and estimate biological age using epigenetic clocks. Experimental treatments such as senolytics, which target senescent cells, have also emerged. Yet despite these remarkable advances, scientists increasingly recognise that ageing is far more complex than once imagined. A new paper by Dr Piotr Chmielewski of Wroclaw Medical University argues that a single universal mechanism does not drive ageing, but rather the interaction of numerous biological processes operating across different levels of organisation.
Published in Biogerontology, the paper, Ageing was never a singular problem in biology: implications for mechanisms, measurements and interventions, challenges the search for a single cause of ageing. Recent discoveries have identified key pathways, including mTOR, AMPK, FOXO and IGF-1, that regulate growth, metabolism and lifespan. At the same time, advances in DNA sequencing have made it possible to study ageing at the level of individual cells. According to Dr Chmielewski, these discoveries have deepened understanding of specific mechanisms but have also highlighted how many overlapping processes contribute to ageing, making it increasingly difficult to view it as one unified biological phenomenon.
For decades, researchers proposed oxidative stress, DNA damage, telomere shortening, mitochondrial dysfunction, epigenetic changes and chronic inflammation as possible primary drivers of ageing. While each contributes to age-related decline, none alone explains the full picture. Instead, the evidence increasingly supports the idea that ageing reflects the gradual disorganisation of a complex biological system. This perspective is reflected in the widely adopted concept of the “hallmarks of ageing”, a collection of interconnected biological characteristics that collectively influence the ageing process rather than a single underlying cause.
The growing use of epigenetic clocks illustrates both the promise and the uncertainty of modern ageing research. These tools estimate biological age by analysing DNA methylation patterns and have been linked to disease risk and mortality. However, researchers still do not know whether they measure mechanisms that actively drive ageing or reflect biological changes caused by other processes. As Dr Chmielewski notes, determining whether reversing epigenetic changes would genuinely rejuvenate the body or merely alter a biomarker remains one of the field’s most important unanswered questions.
The paper also highlights the limitations of translating laboratory discoveries into human medicine. While many interventions extend the lifespan of mice by 20 to 30 per cent, mice differ fundamentally from humans in lifespan, metabolism, tissue organisation, immune function and repair mechanisms. As a result, therapies that appear highly effective in animal models often fail to deliver comparable benefits in people. Increasingly, researchers believe that youth may depend less on avoiding biological damage—which occurs throughout life—and more on maintaining the ability to repair tissues, adapt to stress and preserve normal function.
According to Dr Chmielewski, this shift in thinking may represent one of the most important developments in biogerontology. Rather than asking what causes ageing, researchers are increasingly asking how some organisms preserve resilience, adaptability and function despite continuous damage. From this perspective, interventions such as regular physical activity, calorie restriction and intermittent fasting may promote healthy ageing not by stopping ageing itself, but by strengthening the body’s capacity to adapt and recover. If this view proves correct, future research may focus less on finding a single cure for ageing and more on helping people maintain health and functional independence for as long as possible.
More information: Piotr Paweł Chmielewski, Ageing was never a singular problem in biology: implications for mechanisms, measurements and interventions, Biogerontology. DOI: 10.1007/s10522-026-10436-x
Journal information: Biogerontology Provided by Wroclaw Medical University
