CAN WE CHANGE THE BIOLOGY OF AGING? Part I closed in Barcelona, with a woman who died at 117. María Branyas Morera carried very short telomeres and a bloodstream crowded with mutated clones. Her biological clocks read her more than two decades younger than her chronological age. Old and well, in the same body. Part II goes inside that body. The science of longevity has moved beyond the question of how long a person lives. Researchers are asking why one body loses function decades before another, why some people remain independent into extreme old age, and whether the biological processes behind that difference can be measured, slowed or reversed. The framework is expanding. The original Hallmarks of Aging, published in 2013, identified nine interconnected processes. A 2023 update expanded the framework to twelve. Five have become particularly visible in the emerging longevity market: cellular senescence, chronic inflammation, mitochondrial decline, DNA damage and epigenetic drift. They are now the subjects of laboratory experiments, clinical trials, commercial tests and treatments whose claims sometimes run well ahead of the evidence. The distance between those things matters. A mechanism discovered in a mouse can open an extraordinary line of research without establishing a treatment for a human being. A biomarker can measure a biological pattern without proving that changing the number will extend a life. The story begins with the cells that stop.
THE CELLS THAT STOP Philadelphia, 1961. At the Wistar Institute, Leonard Hayflick and Paul Moorhead were growing human fetal cells for laboratory research. The cultures kept quitting. Under the conditions they studied, normal human cells divided roughly 40 to 60 times before entering a state in which they no longer replicated. The finding challenged the prevailing assumption that cells could continue dividing indefinitely in a suitable culture. The limit became known as the Hayflick limit. Its mechanism emerged later. Telomeres, the protective structures at the ends of chromosomes, shorten as many cells divide. Eventually, the cell registers the damage and stops replicating. What happens next is the more complicated part. The cell does not necessarily die. It can remain metabolically active, releasing inflammatory molecules and other signals into the tissue around it. In younger bodies, senescence serves useful purposes: it helps prevent damaged cells from multiplying and contributes to wound healing. With age, senescent cells can accumulate. Their signals begin to alter the environment in which neighbouring cells must function. Think of a worker who has retired from the job but still occupies the office, sending instructions and influencing everyone who remains. The cell has stopped dividing. It has not stopped having an effect. The experiment that brought senescence into the longevity debate came from the Mayo Clinic. In a 2016 Nature study, Darren Baker, Jan van Deursen and colleagues selectively eliminated senescent cells in genetically engineered mice. In two cohorts, median lifespan increased by 24% and 27%, respectively, with improvements in several measures of health. The result gave researchers a compelling reason to investigate whether clearing senescent cells could delay age-related decline. Human evidence followed, but on a very different scale. In a 2019 pilot study, a Mayo-led team treated nine patients with diabetic kidney disease with dasatinib and quercetin, two drugs being investigated for senolytic activity. Eleven days after the three-day course, biopsies showed reductions of up to 62% in selected senescent-cell markers in fat tissue. The study demonstrated a biological effect in humans; nine patients could not establish whether the treatment would improve health or extend life. The distinction became clearer in 2020, when UNITY Biotechnology's senolytic candidate UBX0101 failed to outperform placebo on the primary pain endpoint in a 183-patient trial for knee osteoarthritis. The idea remains compelling. Its clinical future is unsettled. Clearing cells in a mouse, changing markers in a small human study and producing a meaningful benefit for patients are three different achievements. The word senolytic has travelled quickly into supplement labels and longevity-clinic menus. The evidence behind individual commercial products varies enormously, and the early research does not validate the category as a whole. For now, senescence is one of the most promising areas of ageing biology, with a much longer clinical road ahead.
THE SLOW FIRE In 2000, Claudio Franceschi and colleagues gave a name to a pattern emerging from the study of ageing: inflammaging. Inflammation, the body's essential response to injury and infection, can become chronically elevated as people grow older, contributing to the conditions that increasingly define later life. An acute inflammatory response is meant to rise, do its work and settle. Inflammaging is more like an alarm that never quite switches off. Its sources are numerous: signals from senescent cells, changes in the gut barrier, fat tissue that releases inflammatory molecules, accumulated cellular damage and an immune system shaped by a lifetime of exposure. For years, researchers faced a difficult question. Did inflammation help cause cardiovascular disease, or was it simply another sign of the disease already under way? The answer became more persuasive in 2017, with the results of CANTOS, a large international trial led by Paul Ridker and colleagues. The study enrolled 10,061 patients who had previously suffered a heart attack and had elevated levels of high-sensitivity C-reactive protein, a marker of inflammation. Participants received canakinumab, an antibody that blocks interleukin-1β, or a placebo. Canakinumab did not lower cholesterol. It did, however, reduce the trial's primary composite cardiovascular endpoint by approximately 15% at the tested 150-milligram dose. The result demonstrated that targeting a particular inflammatory pathway could reduce cardiovascular events independently of cholesterol reduction. The trial also carried a warning. Fatal infections were more frequent among patients receiving canakinumab, and the treatment did not produce an overall reduction in all-cause mortality. The drug was not approved as a cardiovascular treatment. The immune system's inflammatory response is both a source of damage and a defence against infection. Suppressing it indiscriminately can exchange one risk for another. That balance sits at the centre of any serious attempt to reduce chronic inflammation. The evidence for everyday interventions is less dramatic than the promise of a new drug, but considerably more established. Regular movement, adequate sleep and maintaining a healthy body composition can influence several metabolic and inflammatory pathways at once. Their effects are not confined to a single biomarker. María Branyas was reported to have unusually low levels of inflammation despite her extreme age. That observation is intriguing, particularly alongside the other features of her biology. It cannot tell us which factor protected her, or whether one factor did so at all. Her case is a remarkable human story, not a controlled experiment.
THE POWER PLANT Every cell in the body depends on energy. Much of the machinery that makes it available sits inside the mitochondria, organelles descended from ancient bacteria that entered into a relationship with our cellular ancestors. The arrangement proved so enduring that mitochondria still retain a small genome of their own. In 1981, researchers at the University of Cambridge published the complete sequence of human mitochondrial DNA: 16,569 base pairs containing 37 genes. Unlike most of our nuclear DNA, mitochondrial DNA is ordinarily inherited through the maternal line. Mitochondria help convert energy from food and oxygen into ATP, the molecule cells use to power their work. Muscle contraction depends on it. So do the brain's signalling networks and the heart's continuous rhythm. Mitochondria also participate in processes beyond energy production, including cellular signalling and responses to stress. Their function can change with age. Mitochondrial damage, altered quality control and declining capacity to meet energy demands are among the changes associated with ageing. The relationship runs in both directions: mitochondrial dysfunction can contribute to cellular damage, while damage elsewhere in the cell can impair mitochondrial performance. The everyday connection is easy to recognise. Climbing a flight of stairs requires energy; so does recovering from the effort. The ability to produce and use energy efficiently helps shape physical capacity, although ageing cannot be reduced to the performance of one organelle. A 2017 study from K. Sreekumaran Nair's group at the Mayo Clinic offered an encouraging finding. Researchers studied 72 sedentary volunteers, dividing them into younger adults aged 18 to 30 and older adults aged 65 to 80. Participants undertook twelve weeks of high-intensity interval training, resistance training or a combination of the two. In the interval-training group, measured mitochondrial capacity in skeletal muscle increased by 49% in the younger participants and 69% in the older group. The researchers also found changes in muscle proteins associated with age, particularly those involved in mitochondrial function. This was a study of exercise and muscle biology, not a demonstration that training reversed ageing throughout the body. Its result was nonetheless striking: older muscle retained a substantial capacity to respond to training. he commercial market has taken the same cellular machinery in several directions. NAD+ now appears in oral powders, chewables, gummies and other supplement formats, alongside intravenous infusions and injections offered by wellness clinics. Products sold under the same name can differ in formulation, route of administration, quality controls and the evidence supporting their use. NAD+, or nicotinamide adenine dinucleotide, is a coenzyme central to cellular metabolism and several processes involved in maintaining and repairing cells. Its biology is well established; the clinical case for many products sold in its name is not. Research into NAD+ and its precursors continues, but evidence for a meaningful, lasting longevity benefit from consumer supplements remains limited. Studies of one formulation or precursor cannot automatically validate another. The regulatory distinction is important. The FDA has specifically warned about compounded injectable NAD+ products made using food-grade ingredients that have not been appropriately processed for sterile drug preparation. The agency has received reports of severe chills, shaking, vomiting and fatigue following NAD+ injections, with some patients requiring medical treatment. These reactions were described as consistent with excessive bacterial endotoxin levels. In a January 2026 warning letter, the FDA also documented an NAD+-containing compounded product with excessive endotoxins and noted that NAD+ was not eligible for the relevant section 503B outsourcing-facility compounding exemptions. Those warnings concern the quality and preparation of injectable products; they do not establish that every NAD+ product is contaminated, or that NAD+ itself is inherently unsafe. Oral supplements occupy a different regulatory category, and the FDA does not approve them for safety and effectiveness before they reach the market. The distinction between a molecule and the product sold in its name is central to the longevity business. NAD+ has a genuine role in cellular biology. Whether a particular powder, chewable or infusion produces a meaningful benefit in people is a separate question—and one that requires evidence specific to the formulation, dose and route of administration. The FDA has issued a specific warning about compounded injectable NAD+ products. The agency is aware of compounders using food-gra The Mayo study required twelve weeks of training. Its most consequential finding came from a familiar intervention, not a promise of youth in a drip.
THE ERRORS THAT ADD UP DNA carries the instructions that allow cells to function, divide and repair themselves. It is also chemically vulnerable. In the early 1970s, Swedish researcher Tomas Lindahl demonstrated that DNA is far less stable than its central role might suggest. It suffers spontaneous chemical damage even without exposure to radiation, toxins or other external insults. Estimates often cited in this field suggest that a human cell may sustain thousands of DNA lesions each day, with figures of up to 10,000 depending on the type of damage counted and the conditions considered. The body survives because repair systems are constantly at work. Lindahl mapped one of these systems; Paul Modrich and Aziz Sancar made foundational discoveries about others. The three shared the 2015 Nobel Prize in Chemistry for mechanistic studies of DNA repair. Repair is remarkably effective, but it is not perfect. Damage can be misrepaired, copying errors can persist, and mutations can accumulate in cells as they divide. The consequences depend on where the changes occur, which genes are affected and whether the altered cell gains an advantage over its neighbours. A 2022 Nature study by Alex Cagan and colleagues at the Wellcome Sanger Institute examined somatic mutations in intestinal stem cells across 16 mammalian species. The researchers found that mutation rates were generally higher in short-lived species and lower in long-lived ones. Across species with widely different lifespans, the number of mutations accumulated by the end of natural life was surprisingly similar, at roughly 3,200 per cell in the study's comparisons. The finding supports a relationship between the pace of somatic mutation and species lifespan; it does not establish a universal mutation count for every human cell or tissue. The consequences of acquired mutations can be seen in the blood. In 2014, Siddhartha Jaiswal and colleagues reported in the New England Journal of Medicine that blood samples from people without diagnosed blood cancer often contained expanding populations of blood cells carrying mutations associated with cancer. The phenomenon became known as clonal hematopoiesis. In the study, these mutations were uncommon in people younger than 40 and became more prevalent with age. They were detected in approximately 9.5% of people in their seventies and 18.4% of those aged 90 to 108. Carriers had an elevated risk of all-cause mortality and cardiovascular disease. The presence of a clone does not mean a person has blood cancer; it means a population of blood cells has acquired a mutation and expanded. María Branyas was reported to carry clonal hematopoiesis. She lived to 117, without the disease that many people associate with cancer-linked mutations. Her survival underscores the distinction between a risk marker and an inevitable outcome. It does not establish that low inflammation protected her from the consequences of those clones, though the relationship between inflammation, clonal expansion and cardiovascular risk is an important area of research. There is a further distinction for the growing market in premium genetic testing. Sequencing the DNA a person inherited can reveal genetic variants present from birth. Clonal hematopoiesis concerns mutations acquired later in particular cell populations. A standard inherited-genome report is not, by itself, a complete account of that ongoing process. Ageing leaves a record in the genome, but the record is not a simple countdown. The same mutation may have very different consequences depending on the cell, its environment and the other changes that have accumulated around it.
THE SCRAMBLED SCORE A neuron and a skin cell carry essentially the same DNA, yet they perform radically different jobs. Their identities depend in part on epigenetic regulation: chemical marks on DNA and modifications to the proteins around which it is packaged help determine which genes are active, when and where. The genome is the score. The epigenome supplies annotations that guide how it is read. With age, some of those patterns change. In 2013, biostatistician Steve Horvath, then at UCLA, published a landmark study of an epigenetic clock. Using DNA methylation data from roughly 8,000 samples spanning 51 tissue and cell types, he identified 353 sites whose methylation patterns could be combined to estimate chronological age across many tissues. The clock helped establish the idea of biological age as something that could be estimated from molecular measurements, rather than inferred from appearance or physical condition alone. Such a number is an estimate built from a statistical model. Different clocks use different sites and methods, and they do not all measure the same thing. Some are designed primarily to estimate chronological age; others are trained around mortality risk, health outcomes or aspects of biological function. Their results are not interchangeable. The possibility of reversing epigenetic ageing has drawn even greater attention. Shinya Yamanaka's discovery that four factors could reprogram mature cells into an embryonic-like state earned him a share of the 2012 Nobel Prize in Physiology or Medicine. Full reprogramming erases cellular identity, which makes it unsuitable as a simple rejuvenation strategy. Researchers began exploring whether cells could be reprogrammed only part of the way, preserving their identity while restoring some younger molecular features. In a 2020 Nature study, researchers led by David Sinclair reported that expression of three reprogramming factors restored aspects of youthful epigenetic patterns and improved vision in mice with optic-nerve damage and in older mice. The result was important proof of concept in an animal model. It was not a treatment for human ageing. A 2023 Cell study from the same research programme examined how repeated DNA damage and repair could disturb epigenetic information in mice. The researchers reported changes in the epigenome and signs of accelerated ageing, with partial restoration following reprogramming. These experiments support a connection between DNA damage, epigenetic organisation and ageing. They do not establish that the same intervention can safely reverse human ageing. The consumer market has moved faster than the clinical evidence. Biological-age tests are sold directly to customers and through longevity clinics, often presenting a single number as a clear reading of the body's condition. The technical limitations are substantial enough to matter. In a 2022 study published in Nature Aging, Albert Higgins-Chen and colleagues examined six prominent epigenetic clocks using repeated measurements of the same blood samples. Technical noise produced deviations of up to nine years between replicates. The result was not that biological age had changed by nine years between tests; it was that the same sample could generate meaningfully different estimates depending on the clock and measurement process. The researchers developed principal-component versions of the clocks that brought most replicate estimates within 1.5 years. A separate study by Leonardo Garma and Miguel Quintela-Fandiño, published in Genome Medicine in 2024, examined the compatibility of existing clocks with newer DNA methylation arrays. The researchers found that results from the tested clocks could be substantially distorted by the newer array platform. The accompanying report from Spain's National Cancer Research Centre described variation averaging about three years, with discrepancies reaching 25 years for some clocks. These were technical differences arising from the relationship between older models and newer measurement platforms—not evidence that an individual's biological age routinely fluctuates by 25 years. A biological-age estimate can be useful in research. Its meaning depends on the clock, the sample, the laboratory platform and the outcome the model was designed to predict. A number on a report is not a diagnosis, and a change in that number does not automatically establish that a person has become healthier or will live longer. The clock is a remarkable instrument. It is also an instrument still being refined.
ONE SYSTEM, FIVE DOORS The five processes do not run in isolation. DNA damage can disrupt the genome, and the repair process itself can disturb epigenetic regulation. Telomere shortening and other forms of cellular stress can push cells into senescence. Senescent cells release signals that sustain inflammation in surrounding tissue. Chronic inflammation can influence the expansion and consequences of mutated blood-cell clones. Mitochondrial dysfunction can reduce the cell's capacity to meet energy demands and contribute to further cellular stress. Each process can affect the others. None, by itself, explains why a person ages as they do. This is the value of the hallmarks framework. It gives researchers a way to map related mechanisms without pretending that one discovery has solved ageing. It also offers a way to judge the claims now being sold to consumers. A senolytic, an infusion, a genetic test or an epigenetic clock may address one part of the biology. Evidence for that part does not establish that the whole system has been renewed. The strongest findings in this field are specific. Senolytic experiments have shown that removing certain senescent cells can improve health and lifespan in mice. CANTOS demonstrated that targeting a particular inflammatory pathway could reduce cardiovascular events in a defined group of patients, while also revealing the risks of suppressing immunity. Exercise training improved measured mitochondrial capacity in older adults. Epigenetic clocks can capture patterns associated with age, while studies of technical noise show why their outputs must be interpreted carefully. The distance between these findings and a commercial promise remains considerable. A shift in a biomarker may be an early signal worth investigating; it is not the same as fewer years lived with disease, preserved independence or a longer life. Those are outcomes that require their own evidence. María Branyas carried short telomeres, acquired mutations and the accumulated marks of 117 years. Her story does not resolve the science. It gives the science a human scale. Longevity is not the absence of every biological defect; it is the question of how a body continues to function amid them, and why some bodies manage that better than others. The instruments are becoming more sophisticated. The interventions are multiplying. The challenge is to keep measurement, mechanism and meaningful benefit distinct as the market grows around them. The biology is only the beginning. Around it, an industry is taking shape—one that brings together medicine, diagnostics, technology, private capital and a new vision of how a human life might be lived. Its ambitions extend far beyond the treatment of disease, into performance, recovery, prevention and the possibility of preserving vitality for longer. Part III examines the world being built around longevity: the science entering clinical practice, the technologies measuring and modifying the body, and the capital flowing towards a future in which ageing itself has become an economic frontier. PART III — THE LONGEVITY ECONOMY: THE NEW HUMAN