Why We Age: The Molecules Driving the Ageing Process

Cutting-edge research seeks to understand at a cellular level how we age. · July 2026

Please note: This article is intended for general educational purposes only. It is not medical advice, nor is it meant to diagnose, treat, cure or prevent any disease. If you are considering any supplement or lifestyle change, please speak with a qualified healthcare professional.

1. The question that keeps me awake at night

Ageing is the one biological process that every person on Earth shares, yet it still feels like one of science's deepest mysteries. We can watch it happen—hair thins, skin loses its spring, joints stiffen, memory flickers, energy fades—but until recently we had only a foggy idea of what was actually going on inside our cells. We knew that time passed, that wear accumulated, and that eventually every organism dies. What we did not know was whether ageing is driven by a handful of master molecules, by thousands of independent failures, or simply by entropy doing its slow, inevitable work.

My own research career has been an attempt to answer a deceptively simple question: why does our whole body age? Not just the skin, not just the heart, not just the brain, but every organ, every tissue, every cell in concert. Because the truth is, ageing is not a collection of separate diseases. It is a systemic process. When we understand the molecules that coordinate that process, we can begin to think about slowing it, repairing it, and perhaps—one day—reversing aspects of it safely.

This blog is a personal account of that search. It begins in an unlikely place: the bubbling, acidic, scalding environments around volcanoes. It winds through a 2008 paper in Nature, through the discovery that a tiny molecule called NAD+ sits at the crossroads of life span and health span, and into the modern science of sirtuins, PARP1, mTOR, and the NAD+ precursors NR and NMN. If you have ever wondered why we age, and whether anything can be done about it, I hope this gives you a window into how scientists like me think about the problem.

2. Why the whole body ages: a systems problem

It is tempting to think of ageing as many small things going wrong at once. The heart ages because arteries stiffen; the brain ages because neurons lose connections; the skin ages because collagen breaks down. But this organ-by-organ view misses the bigger picture. The striking thing about getting older is how synchronised the decline feels. A person in their eighties does not usually have just one failing organ; they have slower wound healing, weaker immunity, less stable metabolism, frailer muscles, and more fragile DNA, all at the same time.

That synchrony is the clue that ageing is regulated, at least in part, by shared signalling networks. Evolution does not care much about how long we live after reproduction, but it cares deeply about how we respond to stress, how efficiently we use food, and how well we repair damage. The same molecular pathways that help a cell survive a famine or a DNA break are the pathways that, over decades, shape the rate at which we age. If we can map those pathways, we can find the control knobs.

In my view, the most powerful way to understand ageing is to look for what I call “nodal points”—molecules or processes that many other ageing pathways feed into. When you find a node, you find leverage. NAD+ turned out to be one of those nodes. Before we get there, though, I need to explain how a fascination with volcanic microbes led me to it.

3. From volcanoes to human cells

My scientific journey began with extremophiles: organisms that live in conditions that would kill most life on Earth. I was fascinated by the archaea and bacteria that flourish in the hot, acidic, metal-rich waters around volcanoes. These organisms survive temperatures above boiling, pH levels strong enough to dissolve metal, and levels of radiation that would shred a human genome. And yet they do not just survive; they thrive.

The question that obsessed me was: how? What molecular tricks allow life to persist under such extreme stress? I spent years studying heat-shock proteins, DNA-repair enzymes, membrane adaptations, and metabolic rewiring. What emerged was a unifying theme: extremophiles do not rely on one super-enzyme. They rely on integrated stress-response networks that detect damage, conserve energy, protect proteins, and repair DNA. When one part of the network is activated, many others follow.

As I looked deeper, I began to notice something surprising. Many of the same stress-response proteins that keep volcanic microbes alive are also present in human cells. We use quieter versions of them, but the architecture is ancient and conserved. That raised an obvious next question: if these networks evolved to help organisms survive short, brutal environmental stresses, could they also influence how long an organism lives under the milder, chronic stress we call ageing?

This line of thinking culminated in a paper I co-authored and published in Nature in 2008. In that study we connected the kinds of stress-survival strategies I had seen in extreme environments to a set of longevity-regulating genes in more familiar organisms. The paper argued, with experimental support, that the molecular machinery organisms use to sense and respond to environmental stress is not separate from the machinery that controls lifespan. They are deeply intertwined. It was a turning point for me. I stopped thinking of ageing as passive wear-and-tear and started thinking of it as a regulated biological process—something we could study, measure, and potentially modulate.

[Author note: Because I do not have the exact title of your 2008 Nature paper, I have described its spirit in general terms. Please feel free to replace this paragraph with the precise findings and citation.]

4. The molecular hallmarks of ageing

Over the last two decades, biologists have converged on a set of “hallmarks of ageing.” These include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled nutrient sensing, mitochondrial dysfunction, cellular senescence, stem-cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis. The list is long, but it is useful because it tells us what to measure.

What excites me is not the list itself, but the connections between the items. Genomic instability triggers DNA repair, which consumes NAD+. Mitochondrial dysfunction produces reactive oxygen species and changes the cell's energy balance. Chronic inflammation spreads damage signals through the blood. Nutrient-sensing pathways decide whether cells should grow or repair. These are not independent failures; they talk to one another.

My research strategy has been to look for the molecular conversations that link these hallmarks. If we can understand the language, we can intervene earlier in the cascade, before the damage becomes irreversible. The rest of this article is about the most important words in that language: NAD+, sirtuins, PARP1, mTOR, NR and NMN.

5. NAD+: the central currency of ageing biology

If there is one molecule I would point to as a master node in ageing, it is nicotinamide adenine dinucleotide, or NAD+. NAD+ is found in every living cell. It was discovered more than a century ago as a cofactor for metabolic reactions, the kind of molecule that helps enzymes transfer electrons during the breakdown of food. For decades it was treated as a dull housekeeping chemical—important, yes, but not glamorous.

That view changed completely with the realisation that NAD+ is also an essential fuel for a family of enzymes called sirtuins and for DNA-repair enzymes called PARPs. Every time a sirtuin deacetylates a protein to regulate gene expression, metabolism, or DNA repair, it consumes NAD+. Every time a PARP enzyme repairs a DNA break, it consumes NAD+. Every time mitochondria talk to the nucleus, NAD+-consuming enzymes are involved.

Here is the critical observation: NAD+ levels decline as we age. By the time a person reaches their fifties or sixties, NAD+ in many tissues may be only half of what it was in youth. Because so many protective enzymes depend on NAD+, that decline has cascading consequences. Sirtuins slow down. PARPs compete for a shrinking pool. Mitochondria become less efficient. The cell switches from maintenance mode to survival mode, and eventually even survival mode fails.

The decline is not random. It is driven by chronic inflammation, DNA damage, obesity, sedentary behaviour, excessive nutrient intake, and disrupted circadian rhythms. In other words, the same lifestyle factors we associate with accelerated ageing also deplete NAD+. This makes NAD+ an extraordinarily attractive target. If we can restore or maintain NAD+ levels, we may be able to keep multiple longevity pathways running at a youthful pace.

Cells make NAD+ through several routes. The de novo pathway builds it from tryptophan, but this is inefficient in humans. The Preiss-Handler pathway converts nicotinic acid (another form of vitamin B3) into NAD+. The most important route for daily NAD+ maintenance is the salvage pathway, which recycles nicotinamide, the by-product of NAD+ consumption, back into NAD+ through an enzyme called NAMPT. NAMPT is the rate-limiting step, and its activity falls with age. When NAMPT slows, the entire NAD+ pool shrinks.

Another age-related culprit is CD38, an enzyme on the surface of immune cells that degrades NAD+. CD38 levels rise with inflammation and age, literally chewing up NAD+ faster than it can be replaced. In animal studies, blocking CD38 can raise tissue NAD+ even without giving precursors. This tells us that both production and consumption matter; raising NAD+ is a balance between making more and wasting less.

6. Sirtuins: the longevity genes that need NAD+

Sirtuins are a family of enzymes that remove chemical tags called acetyl groups from proteins. This sounds technical, but the biological effects are profound. By deacetylating histones and transcription factors, sirtuins influence whether genes are turned on or off. By deacetylating metabolic enzymes, they tune how cells produce and use energy. By deacetylating DNA-repair factors, they help maintain genome stability.

The first sirtuin gene, SIR2, was shown to extend lifespan in yeast. Since then, seven sirtuins (SIRT1–SIRT7) have been identified in mammals, each with distinct localisations and functions. SIRT1 is primarily nuclear and regulates stress resistance, metabolism, and circadian biology. SIRT3, SIRT4 and SIRT5 live in mitochondria and control energy production. SIRT6 is a chromatin-associated enzyme critical for DNA repair and glucose metabolism. SIRT7 influences ribosomal DNA and protein synthesis.

What unites them is their dependency on NAD+. Sirtuins do not work without it. This gives NAD+ a gatekeeper role: when NAD+ is abundant, sirtuins are active and cells invest in repair, stress resistance and metabolic flexibility. When NAD+ is low, sirtuins slow, and cells prioritise short-term survival over long-term maintenance. In this sense, the NAD+-sirtuin axis is a molecular thermostat that reads the energy state of the cell and decides whether to grow or to repair.

Calorie restriction, exercise, and fasting all raise NAD+ and activate sirtuins. That is one reason these interventions are associated with longer, healthier life in animal models. The challenge for modern medicine is to find safe, practical ways to activate the same pathway without asking everyone to live on starvation diets.

Among the sirtuins, SIRT6 has a special place in my mind. It sits on chromatin and helps maintain the epigenetic code, the system that tells each cell which genes to express and which to silence. With age, that code becomes noisy, like a vinyl record played too many times. SIRT6 helps keep the record clean. Mice lacking SIRT6 age rapidly, while mice with extra copies can live longer. SIRT1, meanwhile, is the master regulator of metabolic stress responses, coordinating everything from fat oxidation to circadian rhythms. Together, these enzymes form a surveillance network that keeps cells youthful when NAD+ is plentiful.

7. PARP1: the DNA-repair enzyme that competes for NAD+

Another major consumer of NAD+ is PARP1, a protein that detects DNA damage and recruits repair machinery. When DNA breaks—from sunlight, radiation, toxins, or normal metabolism—PARP1 attaches chains of ADP-ribose to itself and other proteins, creating a molecular flag that says “repair needed here.” That process consumes NAD+.

PARP1 is essential for life. Without it, cells cannot fix DNA breaks and quickly die. But there is a trade-off. As we age and DNA damage accumulates, PARP1 becomes chronically activated, using up NAD+ that could otherwise fuel sirtuins and mitochondrial enzymes. Some researchers describe this as a “tug-of-war” between DNA repair and longevity signalling. If PARP1 hogs the NAD+ pool, sirtuins are starved. If sirtuins are starved, maintenance declines, which leads to more damage, which activates more PARP1.

This is why simply having enough NAD+ matters. It is not just about turning on sirtuins; it is about giving PARP1 enough substrate to do its repair job while still leaving enough NAD+ for the rest of the system. A healthy young cell maintains this balance naturally. An ageing cell does not. Restoring NAD+ is one way to re-establish the balance, though it is almost certainly not the only way.

It is worth noting that PARP enzymes have also become important drug targets in oncology. PARP inhibitors are used to treat certain cancers because they prevent cancer cells from repairing their DNA. In healthy ageing biology, however, the goal is not to inhibit PARP but to give it—and the rest of the NAD+ network—enough substrate to work efficiently. This distinction matters: context is everything in molecular medicine.

8. mTOR: the growth sensor that accelerates ageing when stuck on

If NAD+ and sirtuins represent the “repair and maintenance” side of ageing, mTOR represents the “growth and reproduction” side. mTOR, or mechanistic target of rapamycin, is a kinase that senses nutrients, growth factors, and energy status. When food is plentiful, mTOR is active and cells grow, divide, and build proteins. When food is scarce, mTOR is inhibited and cells switch to maintenance, recycling damaged components through autophagy.

From an evolutionary perspective, this makes perfect sense. When calories are abundant, the body should reproduce and store energy. When calories are scarce, it should conserve resources and repair itself. The problem in modern life is that many of us keep mTOR switched on almost continuously: frequent meals, high protein intake, refined carbohydrates, and low physical activity all maintain mTOR signalling. The result is suppressed autophagy, accumulation of damaged proteins and organelles, and accelerated ageing.

Rapamycin, a drug that inhibits mTOR, extends lifespan in multiple animal models. Calorie restriction and fasting also inhibit mTOR. There is growing interest in whether low-dose rapamycin, intermittent fasting, or other mTOR-modulating strategies can slow ageing in humans. My own view is cautious but optimistic: mTOR is not a simple “bad guy” to shut down completely, because immune function and wound healing depend on it. The goal is to cycle it, to create periods of low mTOR activity that allow autophagy to do its clean-up work.

NAD+, sirtuins and mTOR are not separate dials. They are connected. Sirtuins can influence insulin signalling and mitochondrial function, which feed into mTOR activity. mTOR can influence autophagy, which affects mitochondrial quality and NAD+ metabolism. PARP1 activation drains NAD+, which affects sirtuins, which influence nutrient sensing. Ageing is an orchestra, not a solo instrument.

Exercise is one of the best ways to modulate this orchestra naturally. Physical activity raises NAD+, activates sirtuins, suppresses mTOR transiently, boosts autophagy, and improves mitochondrial quality. In many ways, exercise is the original anti-ageing intervention, and no supplement can fully replace it. The opportunity for molecules like NR and NMN is to complement these lifestyle foundations, especially in older people or those who cannot exercise as much as they would like.

9. NR and NMN: rebuilding the NAD+ pool

Given that NAD+ declines with age, the obvious question is: can we raise it back up? We cannot simply swallow NAD+ itself, because the molecule is too large and charged to cross cell membranes efficiently. Instead, we use precursors—smaller molecules that cells can convert into NAD+. Two of the most studied precursors are nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN).

NR is a form of vitamin B3. It is converted into NMN by an enzyme called Nrk, and NMN is then converted into NAD+ by NMNAT enzymes. NMN sits one step closer to NAD+ in the biosynthetic pathway. Both compounds have been shown in animal studies to raise NAD+ levels in tissues, improve mitochondrial function, enhance muscle endurance, protect against metabolic decline, and even reverse some markers of ageing when given in models of accelerated ageing.

In human trials, NR and NMN have generally been well tolerated and have increased NAD+ metabolites in blood. Some studies have shown improvements in blood pressure, arterial stiffness, muscle function, insulin sensitivity, or markers of inflammation, although the evidence is still emerging and not all trials have been positive. The field is moving quickly, and larger, longer studies are needed to clarify which doses, formulations, and populations benefit most.

My own interest in NR and NMN is not as magic pills. It is as tools to restore a youthful NAD+ environment so that sirtuins, PARPs, and mitochondria can do their jobs again. Think of it as replenishing the fuel in a car that is running low, rather than redesigning the engine. The engine still needs regular maintenance—exercise, sleep, nutrition, stress management—but without enough fuel, even a perfect engine cannot run well.

What about dosing and safety? In published human trials, NR has typically been used at doses from 250 mg to 1,000 mg per day, and NMN from 250 mg to 900 mg per day, with few serious adverse events reported. Common side effects, when they occur, are usually mild gastrointestinal symptoms. However, long-term safety data beyond a few years are still limited, and the optimal dose for any individual depends on age, health status, diet, and lifestyle. In Australia, NR and NMN are regulated differently depending on whether they are sold as complementary medicines, cosmetics, or ingredients in foods; anyone producing or selling them should ensure full compliance with the Therapeutic Goods Administration.

10. Why the whole body responds

One of the most satisfying aspects of NAD+ biology is that it explains, at least partially, why interventions can have whole-body effects. Because NAD+ is used in virtually every cell type, restoring it can improve muscle, brain, heart, liver, skin, and immune function simultaneously. This is very different from a drug designed for one organ or one disease.

Consider the skin, which is both a visible barometer of ageing and an active metabolic organ. Skin cells experience UV-induced DNA damage, which activates PARP1, depletes NAD+, and suppresses sirtuins. The result is slower repair, more senescent cells, reduced collagen production, and wrinkles. Supporting NAD+ levels in skin cells may help them mount a better repair response. That is part of the rationale behind NAD+-boosting skincare and nutraceutical strategies, though again, the science is still developing.

Similarly, the brain is highly dependent on mitochondrial energy. Neurons consume enormous amounts of ATP, and much of that ATP production is regulated by NAD+-dependent processes. Age-related NAD+ decline may make neurons more vulnerable to energy failure, DNA damage, and inflammation. This is why cognitive ageing and neurodegeneration are active areas of NAD+ research.

The immune system is another whole-body player. Immune cells need NAD+ for energy, signalling, and the resolution of inflammation. Chronic inflammation, or “inflammaging,” both depletes NAD+ and is fuelled by NAD+ decline. Breaking that loop is one of the central goals of ageing research.

What does this mean in practice? I think of ageing interventions as a pyramid. The base is sleep, exercise, nutrition, stress management, and social connection. The next layer is targeted supplementation that supports NAD+, such as NR or NMN, ideally informed by biomarkers. Above that are more specific pharmacological tools that modulate mTOR, remove senescent cells, or address particular risk factors. The pyramid reminds us that no molecule works in isolation; the goal is to create an internal environment where every repair system can function.

11. What I believe the future holds

We are at an extraordinary moment in the biology of ageing. For the first time in history, we have plausible molecular targets, measurable biomarkers, and early clinical data. I believe the next decade will bring three major advances.

First, we will develop better ways to measure NAD+ and related metabolites in different tissues. Blood tests are useful but imperfect. Techniques to assess NAD+ in muscle, brain, skin, and immune cells will help us personalise interventions.

Second, we will learn how to combine NAD+ precursors with other lifestyle and pharmacological interventions. Exercise, fasting, mTOR modulation, sirtuin activators, senolytics, and mitochondrial enhancers may work synergistically. The future of ageing medicine is almost certainly combinatorial.

Third, we will move from slowing ageing to partially reversing aspects of it. The discovery that ageing is accompanied by reversible epigenetic changes, and that cells can be reprogrammed to a more youthful state without losing their identity, suggests that the biological clock is not a one-way street. We must be cautious—reprogramming is powerful and potentially risky—but the direction of travel is clear.

12. A personal reflection

When I started out studying life in volcanic hot springs, I did not imagine I would end up working on human ageing. But the same principles apply: life survives by sensing stress, conserving energy, and repairing damage. The organisms that do this well live longer. The cells that do this well stay younger. The molecules that coordinate these responses are ancient, conserved, and within reach of modern medicine.

I am often asked whether we will ever cure ageing. My answer is that ageing is not a disease to be cured in the traditional sense. It is a set of biological processes that we are learning to understand, measure, and modulate. The goal is not immortality; it is health span—more years of vigorous, independent, joyful life. If we can give people an extra decade of good health, that would be one of the greatest achievements in medical history.

Another question I hear often is whether we should be worried about interfering with the natural order. My response is that humans have been interfering with biology to improve health for millennia: sanitation, vaccines, antibiotics, eyeglasses, and insulin are all ways we have chosen to alter what nature alone would provide. The ethics of ageing research are real and important, but they centre on safety, equity, and honesty about the evidence, not on a vague reverence for ageing itself. We should move forward carefully, transparently, and with the goal of reducing suffering.

13. How we hunt for the molecules of ageing

In my laboratory, we do not start with a drug and hope it works. We start with a question: which molecule is drifting out of balance first, and can we correct it safely? To answer that, we use a toolkit that spans from single cells to whole animals.

At the simplest level, we grow human cells in dishes and stress them. We expose skin fibroblasts to ultraviolet light, or endothelial cells to high glucose, or neurons to inflammatory signals. Then we measure NAD+, NADH, the activity of sirtuins and PARPs, mitochondrial respiration, and the production of reactive oxygen species. These experiments tell us whether a particular insult depletes NAD+ and whether giving NR or NMN can restore function.

We also use organoids—miniature three-dimensional tissues grown from stem cells—to study ageing in something closer to a real organ. A brain organoid can form layers of neurons and support cells; a skin organoid can produce melanocytes and keratinocytes. In these models we can watch how NAD+ decline changes tissue architecture over time. They are not perfect, but they are far more realistic than a flat layer of cells.

Of course, the gold standard remains animal studies, usually mice. We can genetically modify mice to lack or overexpress specific enzymes, feed them different precursors, put them on exercise or calorie-restriction protocols, and measure lifespan and health span. Health span is harder to measure than lifespan. We test muscle strength, coordination, memory, immune responses, wound healing, metabolic flexibility, and even the texture of their fur. The goal is not simply to help a mouse live longer in a cage; it is to help it live better.

Finally, we translate these findings to humans using biomarkers. Blood samples give us metabolomic profiles, inflammatory markers, and epigenetic clocks. Epigenetic clocks are perhaps the most exciting development: they read patterns of DNA methylation to estimate biological age. A person might be sixty chronologically but fifty-five or sixty-five biologically, depending on their lifestyle and genetics. If an intervention can shift the epigenetic clock backward, even by a small amount, it is strong evidence that we are not just treating symptoms but changing the ageing process itself.

This pipeline—cells, organoids, animals, humans—takes years, sometimes decades. It is slow, expensive, and occasionally frustrating. But it is the only way I know to separate genuine anti-ageing biology from hype. In a field as seductive as longevity research, intellectual rigour is the most important tool we have.

14. Bottom line

• Ageing is a systemic, regulated process, not just a collection of organ failures.
• NAD+ is a central molecular node that declines with age and supports sirtuins, PARP1, and mitochondrial function.
• Sirtuins are longevity enzymes that require NAD+ to regulate gene expression, metabolism, and repair.
• PARP1 consumes NAD+ to repair DNA; chronic DNA damage can deplete NAD+ and starve sirtuins.
• mTOR is a nutrient sensor; keeping it chronically active suppresses repair processes such as autophagy.
• NR and NMN are NAD+ precursors that can raise NAD+ levels and are being studied for their effects on ageing and metabolism.
• The most powerful strategy will likely combine NAD+ support with exercise, nutrition, sleep, and other targeted interventions.

15. References and further reading

[Author note: Please add your own key papers, including the full citation of your 2008 Nature paper and any recent NR/NMN/mTOR/sirtuin reviews you would like readers to explore.]

Disclaimer: This blog reflects the author's scientific perspective and is not intended as medical advice. Statements about NAD+, NR, NMN, sirtuins, PARP1, mTOR and ageing are based on published preclinical and early clinical research and have not been evaluated by the Therapeutic Goods Administration (TGA) or the Food and Drug Administration (FDA). Always consult a healthcare professional before starting any new supplement or health regimen.