Aging & Fitness Part 2: On the Biology of the Aging Body!

In the linklast blog I looked at the magnitude of the effect of ageing on athletic performance, today I examine why fitness declines with age. In the next blog, I will examine how to minimise or reverse this!

We can divide this discussion into three major areas: your genes, your muscle mass, and your metabolism… but let’s start with the big question: why do we age at all?

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Why Do We Age?

Ageing takes place in every living creature basically one cell at a time. In short, if your cellular DNA damage (e.g. from oxidative stress) is greater than your cellular repair (e.g. from stem cells) then your organs will deteriorate and eventually something (e.g. your heart) will fundamentally break… and you will die! Sorry, I hope this does not come as a shock!

Every living thing is subject to the same limitation of ageing cells (except perhaps these which might have tricked nature?? linklink).

In fact, lifespan itself is reasonably predictable across the animal kingdom, with three major traits having a strong influence:

Brain weight, body weight, and resting metabolic rate.

In fact, there is an equation as follows: life span = $5.5E^{0.54}S^{-0.34}M^{-0.42}$ where E=brain weight, S=body weight in grams, and M=metabolic rate kcal/g/hr.

In humans, many insurance companies try to estimate life expectancy using a few headline factors like linkthis one.

So if ageing is essentially a process when mechanisms of repair slow down below the rate of cellular damage, then the ageing process probably depends mostly on our ability to repair damaged chromosomes in cells, right? Indeed, we can get a measure of this in a few ways, such as stem cell activity.

For example, neural stem cells are important for ongoing generation of new neurons in specific regions of the brain but play a limited role in damage repair. Muscle stem cells (or satellite cells) play a small role in muscle maintenance but vigorously engage in regeneration after injury. Haematopoietic stem cells and intestinal stem cells do both, contributing to ongoing production of differentiated cells and also repairing tissue.

In the early years of growth, stem cells are highly active and contribute to tissue formation. During the reproductive phase of life, stem cells maintain and repair tissues. But beyond reproductive maturity (when cell and tissue functions are predicted to be under little evolutionary pressure): stem cell functionality declines.

OK, that seems clear, but why does cellular damage occur in the first place? This is sadly a legacy of using oxygen as a fuel (evolution kick-started this in eukaryotes). Oxygen is highly energetic which can be a good thing but also dangerous. The rise of oxygen concentrations in the Earth’s atmosphere and oceans was one of the most important events in life history, and is thought to have triggered the origin of eukaryotic life (linkand sexual reproduction!).

Many oxidative reactions (loss of electrons) take place within cells and result in highly reactive “free radicals” leading to damage of cell components such as membranes (a theory first proposed by Denham Harman). Mutation of mitochondrial DNA impairs the function of proteins in the organelle’s respiration machinery, enhancing the production of DNA-damaging oxygen radicals, increased expression of proinflammatory genes, tissue inflammation and ultimately dysfunction and degeneration.

Mutations accumulate in stem cells, contributing to the age-associated decrease in homeostasis and regenerative potential. These are replication errors made by the mtDNA polymerase and oxidative damage. During the lifetime of an individual, both inherited and de novo mutations formed early in life can clonally expand, reflected in the mosaic nature of respiratory chain dysfunction observed in ageing tissues. Accumulating evidence from the last three decades shows that mtDNA mutations, be they point mutations or large-scale deletions, increase with age both in humans and mammalian model organisms.

So that’s my attempt at explaining ageing. Now let’s look at three big mechanisms of ageing: genes, muscles, and metabolism (mitochondria).

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Mechanism #1: Your Genes (Telomeres)

One major contribution to ageing is genetics. For example, identical twins have life spans more similar in length than do non-twin siblings. By indeed looking at twins, it was estimated that lifespan could be about 12%-25% genetic. 30% of longevity variation in female mice is genetically determined (for males it’s 20%). Long-lived people tend to have more ‘T’s in the single nucleotide polymorphisms FOXO3 gene ‘rs7412,’ less ‘C’s in the cholesterol-related APOE gene ‘rs429358’, and more ‘G’s in ‘rs2802292’.

Fifty years ago, Leonard Hayflick and Paul Moorhead discovered that many human cells have a limited capacity to reproduce themselves in culture by dividing. They found that after 40 and 60 cell divisions, they can divide no more, and this has been called the “Hayflick Limit”. It seems that what determines the Hayflick Limit for dividing human cells is the length of a cell’s telomeres. These are repeated segments of DNA on the ends of chromosomes.

You can therefore measure longevity using telomeres. The number of repeats in a telomere determines the maximum life span of a cell, since telomeres lose a little bit of their length during each cell division. Since replicative DNA polymerases are not able to replicate telomeres, and telomerase (specialised DNA polymerase that could replicate telomeres) are not expressed in normal mammalian somatic cells, telomeres become too short to replicate after a fixed number of cell divisions. Eventually, the cell will stop dividing and die.

Research has shown that telomeres are vulnerable to genetic factors that alter an organism’s rate of ageing. In humans, variations in a gene known as TERC has been linked with an increased rate of biological ageing.

We can actually count up the telomere base pairs. We are born with telomeres between 5–12,000 base pairs long; whereas mice have about 50,000 base pairs… but they lose 7,000 base pairs per year compared to 15–50 base pairs per year in humans. A greater rate of telomere shortening therefore suggests a faster pace of ageing.

However, your body will respond to exercise. Consider these two studies:

In a study of 2401 twins (linkArch Intern Med. 2008), researchers found study participants who spent more than 3 hours each week engaged in vigorous physical activity (such as lifting weights) had longer telomeres than subjects 10 years younger, suggesting that individuals who eschew placing a vigorous load on their body may wind up biologically older by 10 years.

A second study from the Mayo Clinic compared groups of younger (18–30 years old) and older (65–80 years old) adults who did one of three kinds of exercise regimes for 12 weeks: resistance (strength building) exercises; high-intensity interval training on stationary bikes; or a combination of light resistance training and moderate-paced cycling (linklink). Older participants experienced dramatic improvements at a cellular level. Scientists found that after just 12 weeks, almost 400 genes in the older participants who did HIT training on bikes were working differently. In the younger group, only 274 genes changed. In the older group, a change was seen in only 33 genes for the weight lifting group and only 19 genes in the moderate exercise group.

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Mechanism #2: Your Muscle Mass

Another big factor behind ageing is muscle size (and muscle efficiency); i.e., a reduction in muscle mass as we get older. Muscles get thinner and weaker BUT this effect is massively influenced by exercise. After the age of 30, adults typically lose up to 10 oz. of muscle mass per year, just over 8 lbs. per decade (Evans & Rosenberg, 1991). This is due to both atrophy of exercise muscle fibres, and to degeneration of spinal motor neurons, usually the type II, fast-twitch units. Many adults lose 30% of their muscle cells between the ages of 20 to 70 (so sarcopenia begins at 20! If you stop sports then).

Also with age, the number of cross-linkages within and between collagen molecules increases, leading to crystallinity and rigidity, which are reflected in a general body stiffness. There is also a decrease in the relative amount of hexosamine–collagen ratio, which has been investigated as an index of individual differences in the rate of ageing.

But again, exercise reduces this decline, and both endurance (cardiovascular) and strength (resistance) training can help (see linkSolberg and linkBouaziz).

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Mechanism #3: Metabolism (Mitochondria)

Loss of muscle mass above is not a very informative answer on its own. We need to understand what underlines the loss of muscle mass. The answer is mainly a decline in muscle mitochondrial protein synthesis (and mitochondrial gene expression). In one study, skeletal muscle demonstrated a higher (40%) mitochondrial protein synthesis rate in 24-year-olds compared with middle-aged and older individuals (linkref).

Again, the good news is exercise training is mitoprotective and anti-sarcopenic. Exercise, both in the forms of endurance and resistance training, improves ETC electron flux and mitochondrial oxidative coupling. Specifically, resistance training increases the ratio of complex IV/complex I + III, which in turn minimises electron leakage and thus ROS generation from complexes I and III, the main cellular sources of superoxide. At the level of mtDNA, this decreases oxidative damage of mtDNA and reduces the prevalence of deletion mutations.

In addition, when resistance training is coupled with endurance training, or with endurance training alone, mtDNA abundance, mitochondrial protein synthesis, and mitochondrial biogenesis all increase. At the level of muscle fibres, these exercise-induced changes prevent age-associated aberrant COX−/SDH++ phenotypes and preserve type II muscle fibres, altogether reducing muscle wasting with age (aka sarcopenia). linkLink for more info.

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Mechanism #4: Cellular Repair

The Master Equation: Damage vs. Repair

To truly understand how exercise alters our biological clock, we need to look at the master equation of ageing:

Ageing = (Rate of Cellular Damage) – (Rate of Cellular Repair)

As we saw earlier, damage happens simply by being alive—breathing oxygen, metabolising food, and exposure to UV light all create oxidative stress. Modern geroscience identifies that this damage manifests across several specific biological pathways, commonly referred to as the hallmarks of ageing (linkLópez-Otín et al., 2013; 2023). In our youth, our repair rate is astonishingly high, but as we get older, cellular repair naturally begins to slow down across these domains:

• Epigenetic Alterations: Gene expression changes over time without altering the underlying DNA sequence. This includes DNA methylation, which drives the biological “epigenetic clocks” that measure true tissue age.
• Cellular Senescence: Stressed cells become “senescent” or “zombie cells.” They stop dividing but remain active, secreting a toxic cocktail of inflammatory cytokines (the Senescence-Associated Secretory Phenotype, or SASP) that accelerates ageing in surrounding tissues.
• Deregulated Nutrient Sensing: The cellular pathways responsible for longevity and energy management degrade. This includes the overactivation of mTOR (associated with rapid ageing) and the decline of AMPK and sirtuins.
• Loss of Proteostasis: The body’s protein quality-control machinery fails, leading to the accumulation of misfolded and aggregated proteins—a primary driver of neurodegenerative diseases.
• Altered Intercellular Communication (Inflammaging): A chronic, low-grade, sterile inflammation develops. This systemic baseline inflammation drives tissue breakdown and immune decline (immunosenescence).
• Macroautophagy Compromise: The cellular “waste clearance” system declines, meaning cells can no longer efficiently clear out damaged organelles and proteins.
• Microbiome Dysbiosis: The gut microbiome loses diversity and shifts toward pro-inflammatory bacterial strains, impacting systemic metabolism, immunity, and brain function.

Crucially, if you lead a sedentary lifestyle, your body operates on a “use it or lose it” basis. It assumes you do not need a highly active, metabolically expensive repair system, so it dials down repair activity to conserve energy. The daily damage begins to significantly outpace the repair, and the physical signs of ageing accelerate.

The Ultimate Paradox of Exercise

A hard training session actually causes acute cellular damage. It tears muscle fibres, depletes energy, and creates a massive, temporary spike in oxidative stress and free radicals. But this is your secret weapon. This brief, intense pulse of stress triggers a biological phenomenon known as hormesis—a highly beneficial over-compensation response to a mild stressor.

When you make exercise a consistent habit, this acute stress constantly “wakes up” your cellular repair machinery. It forces your body to fortify itself against future stress, shifting your biological age across all major ageing pathways:

In short, a lifelong exercise habit shifts the mathematical equation of ageing firmly back in your favour. It doesn’t stop the daily damage of being alive, but it guarantees your cellular repair rate remains fiercely competitive, matching the insults of time blow for blow.

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Conclusion & Summary

Ageing is a consequence of cumulative damage in all cellular constituents, especially DNA, often from oxygen itself. Every day there are thousands of insults that affect DNA, including endogenous factors (such as metabolism) and exogenous factors (like diet, radiation, toxic substances). Each of the ~10¹³ cells in the human body receives tens of thousands of DNA lesions per day; the most pervasive environmental DNA-damaging agent is ultraviolet light (UV) where residual UV-A and UV-B in strong sunlight can induce ~100,000 lesions per exposed cell per hour.

Only a minimal amount (less than 0.02%) accumulates as permanent damage, while the rest is miraculously repaired by linkhundreds of mechanisms. However, if only one important gene is not repaired and its function is vital, such as a tumour suppressor, then this could result in chromosomal aberrations causing certain cells to transform into cancer cells (linklink).

As Benjamin Franklin said “Nothing is certain except death and taxes“. However, that does not mean longevity occurs at a fixed rate. What you do now makes a big difference. Try that linklife expectancy calc again! Now we understand a lot of the mechanisms, we will look at what specific exercises we should undertake in the next blog.

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Citations and Further Reading