• Emilina Lomas

What happens to the body as we age

Aging is inevitable. As Benjamin Franklin famously said, ‘there are only two things certain in life: death and taxes’. Under the title death we also, inevitably, have aging. As we age, our body changes. A range of hormonal and physiological changes occur that alter how we move, how we feel and how we look. So what actually happens to our bodies as we age? And what can we do to prevent it?


What happens to our body as we age?

A landmark study published in the journal Cell in 2013 analyzed the key biochemical changes that characterize aging in humans. The researchers summarized their findings into nine biological categories, the ‘hallmarks’ of aging. To explain what happens when we age, we will explore these nine categories set out in the Cell study to assess what you can do to prevent premature aging and feel optimal as you get older.


The hallmarks can be separated into three different stages: primary, antagonistic and integrative; to understand how the hallmarks interact and compound the effects of each.














Source: Cell The Hallmarks of Aging 2013

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STAGE 1 - PRIMARY HALLMARKS

The first stage of aging can be characterized as the processes that cause cellular damage. These are the primary hallmarks of aging.


1. Genomic instability

As we live our day to day lives, our DNA is constantly being damaged by environmental external stressors. If you go out in the sun, harmful UV rays are damaging your DNA, if you smoke cigarettes, if you live in an area of high pollution or if you are absorbing dangerous chemicals from cleaning or skincare products, you are damaging your DNA. So what happens when you damage your DNA? Luckily, we have enzymes that are able to effectively target and repair nuclear and mitochondrial DNA damage.


However as we age, this repair system becomes less effective and DNA damage accumulates, and when it does, cell replication machinery (the cellular mechanisms responsible for DNA replication) may misread the information in the DNA, causing a mutation. When a mutation or accumulated DNA damage occurs, a pathway known as cell apoptosis begins where the harmful cells destroy themselves so as not to replicate and cause damage to the host.


When cells escape apoptosis or continue to mutate, host health is compromised. The most common disease associated with defective responses to DNA damage is cancer, and less common diseases such as Hutchinson-Gilford progeria syndrome (HGPS). As well as an increased risk of disease, DNA damage also accelerates aging.


So what can you do to prevent genomic instability? Unfortunately you can’t prevent it, like the other hallmarks genomic instability is an inevitable component of life drawing to a close. There are certain lifestyle and environmental habits you can adopt to slow down this hallmark like avoiding sun exposure, using chemical-free products, not smoking and exercising. However even if these are adopted, damage still occurs through free radicals called reactive oxygen nitrogen species (RONS) that exist as a result of normal bodily functions.


Exercise has been shown in research to help maintain genomic stability. It does this by boosting DNA repair mechanisms by acting as an antioxidant, according to researchers of a 2008 study. The study, published in Free Radical Biology and Medicine, concluded that exercise has anti-inflammatory, antioxidant properties due to the spike of antioxidant enzymes that occur post-exercise to repair the muscle damage and oxidative stress. Essentially the small spike of inflammation and oxidative stress that occurs during exercise is met with a potent anti-inflammatory and antioxidant response that has the ability to promote genomic stability, when engaged in consistently.


2. Telomere attrition

Telomeres are sequences of DNA that act as protective caps at each end of a chromosome. They protect the chromosome from damage to uphold the structural integrity of the chromosome and they limit the total number of replications a cell can make, to prevent mutations.


As you probably learned in school, DNA strains bond together to make a sequence. The telomere acts as a sort of secret code word to other telomeres to ensure the chromosomes are only bonding with each other. If a telomere is dysfunctioning or damaged, the chromosome could bond with other molecules, which can be harmful. However, as in the previous case of genomic instability, enzymes exist that repair faulty telomeres to prevent this from happening.


Telomeres limit cell replications as a preventative measure against mutations, which can lead to diseases like cancer. Each time a cell divides, the telomeres get shorter from each end of the chromosome, until the telomere is all but lost and cell division ceases to exist. When the telomere dwindles, the chromosome becomes exposed to damage and our cells stop functioning properly.


Typically, telomere length in humans decreases at a rate of 24.8 to 27.7 base pairs per year, according to a study published in the journal Lancet in 2005. Telomere attrition is accelerated by lifestyle factors including overweight and obesity, smoking, poor diet, all causing oxidative stress and inflammation. Researchers of the Lancet study found a statistically significant relationship between obesity and telomere attrition, with obese women having telomeres 240 base pairs shorter than lean women. Similarly, a study set to be published in March 2020 found that antioxidant-rich food consumption was associated with telomere length and stability amongst participants.


Engaging in regular physical activity has been shown in research to support telomere length, particularly among older adults. As per a study published in 2017 by Arsenis et al, the relationship between exercise and telomere length is multifaceted. A number of mechanisms are responsible for the effect of exercise on telomere length including reducing oxidative stress and inflammation, increasing the number of skeletal muscle satellite cells and upregulating protective proteins.


3. Epigenetic alterations

Epigenetics is the modification of gene expression that can switch genes on or off. A helpful way to think about this point is that in our bodies, all of our DNA is the same, yet all of our organs have separate roles: pancreatic cells, liver cells, skin cells etc. Epigenetics tells each cell what to become by turning it ‘on’ or ‘off’. As we age, epigenetic alterations - also referred to as epigenetic drift - occur that can suppress cell functionality. A common alteration that occurs is the switching off of immune cells, which is why as we age we become more vulnerable to infections and pathogens.


Epigenetic alterations cause more than a downregulation of cell functionality, they can also damage DNA through histone modification, methylation patterns and more. To prevent epigenetic alteration, some preliminary research has proposed the idea of dietary manipulation. One study published in Biochemistry and Pharmacology in 2010 argued that our diets heavily influence gene expression by way of exacerbating or decreasing inflammation, a precursor to epigenetic alterations.


Alongside dietary manipulation, a range of environmental and lifestyle factors can influence epigenetic alterations. Regular exercise alters the gene expression pattern in multiple tissues and can modify DNA methylation patterns, promoting epigenetic functionality, as explored in a 2014 study. One such epigenetic modification is the remodeling of the chromatin, caused by the increase of brain-derived neurotrophic factor (BDNF) during physical activity.


4. Loss of proteostasis

Proteins are molecules integral to human health and affect all cellular functions in the body from the skin to the liver. The role of protein depends on their amino acid structure, but can be anything from an antibody to an enzyme.


Protein homeostasis or proteostasis is the process of regulating cell protein to maintain homeostasis. Protein homeostasis is maintained by a number of complex integrated pathways within the cell to regulate the lifecycle and role of proteins, also known as the proteostasis network. This network also helps to produce new healthy proteins to go to work as an antibody, enzyme, etc.


As we age, proteostasis becomes less accurate and stable. Old proteins are not properly eliminated, enough new proteins are not produced, new faulty proteins are produced that are unable to perform their role. Faulty proteins have been linked to diseases like Alzheimer’s and Parkinson’s, in which the proteins bond together and destroy neurons. These proteins aggregate and accumulate, becoming toxic.


However, lifestyle factors can influence the functionality of proteostasis as we age. A study published in 2011 analyzes how metabolic signalling pathways can modulate the proteostasis network to prevent the toxic accumulation of proteins or faulty proteins. The researchers concluded that dietary restriction and reduced insulin/insulin-like growth factor (IGF-1) activity help to extend lifespan and functionality of proteostasis.


Studies show that regular exercise helps to improve proteostasis by inducing autophagy. Autophagy is the turning over of damaged cells to regenerate new, healthier cells. If a build up of proteins occurs, as is common in aging, autophagy helps to remove them. A clinical trial found that resistance training increased muscle protein synthesis and decreased protein degradation through the activation of autophagy.


STAGE 2 - ANTAGONISTIC HALLMARKS

The second stage of aging can be characterized as the responses to the cellular damage caused by the primary hallmarks. These are the secondary hallmarks of aging.


5. Deregulated nutrient sensing

On a moment by moment basis, our cells are adapting to the amount of nutrients available within the body, signalling hormones to eat more, stop eating, digest or metabolize, amongst others. When we age, we experience deregulated nutrient sensing. This is when our cells become less accurate at detecting nutrient stores, and thus less effective at metabolizing the nutrients consumed. This can lead to weight gain, hormonal problems and metabolic conditions.


There are four key proteins associated with aging: insulin/IGF-1, rapamycin (mTOR), AMP-activated kinase (AMPK) and sirtuins. As mentioned in hallmark four, reduced insulin/IGF-1 has been shown in research to extend lifespan and promote longevity. Too much mToR is associated with premature aging and metabolic conditions like diabetes, and studies have shown that inhibiting mTOR pathways helps to slow aging. Levels of AMPK are higher during periods of fasting or calorie restriction, helping to regulate the metabolism. A 2017 study published in Cellular Metabolism linked AMPK with longevity and lifespan, and it can be manipulated by controlling caloric intake.


Sirtuins are proteins that become nicotinamide adenine dinucleotide (NAD+) that help to regulate gene expression and boost longevity. The sirtuin pathway has been shown in research to be closely connected to aging, by protecting cell division, cell metabolism and regulating the stress response. Sirtuins can only function when NAD+ is present, a coenzyme that decreases with age.


So how can you increase NAD+? A recent study published in Physiological Reports found that in a 12 week trial, resistance training increased NAD+ by 30 percent in older adults. Regular exercise is also shown to have a beneficial effect on glucose metabolism and insulin sensitivity.


6. Mitochondrial dysfunction

Mitochondria are the powerhouses of cells. They metabolize the nutrients consumed to create energy for the cells, producing around 90 percent of the energy cells need to survive. As well as providing the energy for the cells, mitochondria are also responsible for breaking down waste, producing chemicals for signalling and cell apoptosis. As we age, our mitochondria become less functional: producing energy less efficiently and releasing harmful reactive oxygen species. According to a study published in 2018, reactive oxygen species causes DNA mutations, inhibits proteostasis, accelerates sarcopenia and suppresses the immune system.


To uphold the functionality of mitochondria, increasing NAD+ through supplementation or lifestyle alterations has been shown in research to slow down mitochondrial damage. One such lifestyle alteration involves increasing your amount of physical activity. A study published in the journal Diabetes found that individuals who regularly exercise had boosted mitochondrial functional compared to those who were sedentary.


7. Cellular senescence

Cellular senescence occurs as a result of telomere attrition, influenced by a range of other mechanisms like inflammatory cytokines, oxidative stress and hormonal changes. With age, increasing number of cells become senescent; they cease to divide or do their job, secreting inflammation and infecting surrounding cells. Senescent cells are highly inflammatory and reduce the functionality of cells, which leads to tissue damage and an increased risk of disease.


Typically harmful cells are eliminated by cell apoptosis, however with age, this process becomes less effective and senescent cells accumulate causing chronic inflammation. A recent study found that removing senescent cells in mice was associated with increased lifespan and longevity. If you want to reduce senescent cells, the answer may be more simple than you may expect; a study published in Exercise Immunology Review found that in a clinical trial, participants who were regularly physically active had less accumulation of senescent cells than those who were sedentary.


STAGE 3 - INTEGRATIVE HALLMARKS

The third stage of aging can be characterized as the processes that occur as a result of the primary and secondary stages. These are the final hallmarks of aging.


8. Stem cell exhaustion

Stem cells are cells that have the ability to develop into many different cell types, depending on epigenetic regulation, and can be used to repair and replace tissue, and replace red and white blood cells. Stem cell exhaustion refers to a reduction of stem cell activity, in which stem cells are unable to repair or replace damaged tissue or blood, causing degeneration. A number of processes lead to stem cell exhaustion including all the aforementioned hallmarks of aging, particularly telomere attrition and the inflammation spread by senescent cells.


If you want to reduce the likelihood of stem cell exhaustion, it is necessary to target the catalysts: the primary and secondary hallmarks of aging. Aside from the genetic component, this can be done through lifestyle adjustments like increasing physical activity, fasting, improving diet quality, managing stress and avoiding pollutants. A 2019 study published in Frontiers in Endocrinology found that obese participants had reduced functionally active stem cells regardless of age, which damaged mitocondria content and function and altered gene expressions.


9. Altered intercellular communication

As in the case of stem cell exhaustion, as we get older, inflammation increases in the body which accelerates aging in a process known as inflammaging. As an attempt to regulate some of this inflammation, cells activate a chemical called nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) (quite the mouthful!). This chemical regulates inflammation which is positive, but increasing NF-kB can have some negative consequences. A study published in the journal Nature in 2013 showed that when levels of NF-kB are high, a regulatory hormone in the brain is inhibited, resulting in sarcopenia, wrinkles and accelerated aging.


Old age causes a reduction in the communication between the neuronal, neuroendocrine and endocrine systems. The inflammaging phenotype is a key example of impaired communication, emitting inflammatory cytokines, causing healthy cells to suffer, which in turn creates a cycle of cellular degeneration and accelerated aging.


The physical effects of aging


So now you know the nine biological categories associated with aging. You understand the effects of aging at a cellular level, but you’re left wondering what the physical effects are, how will my age affect my body?


Unfortunately, research shows that age causes a decline in mobility, weakened muscular strength, reduced muscle and bone mass and a decrease in flexibility. However it’s not all doom and gloom. Your lifestyle habits dictate the speed at which aging occurs, and to what extent.


Age-related muscle loss and a loss of bone density is a condition known as sarcopenia. According to a study that examined muscle tissue changes that occur with age, we lose up to 8 percent of our muscle mass every ten years after 30. A loss of muscle mass results in reduced mobility and strength, poor balance, a decreased metabolic rate and accelerated aging. So how can you retain muscle mass as you age? Exercise.


Why exercise is the answer


If you want to build and retain muscle mass as an older adult you need to incorporate resistance training. Lifting weights and doing resistance based workouts helps to increase bone density and muscle mass via the process of hypertrophy. When you resistance train you cause muscle damage, which stimulates muscle protein synthesis, resulting in muscle tissue growing bigger and stronger to prevent the same stimuli from damaging the muscle again. When you have a healthy amount of muscle mass and physical strength, this compounds to prevent age-related occurrences like poor balance, falling related injuries, stiff joints and more.


A large scale study published by the Journal of the American Medical Association (JAMA) looked at 40 randomized controlled trials that included more than 22,000 older adults. The study wanted to test whether regular exercise increased or decreased an individual’s risk of falling. The study found that when compared to older adults that did not exercise regularly, those who exercised regularly (for more than one year) had a 12 percent relative reduction in falls and a 26 percent reduction in falls that caused a serious injury. The best results in the study were associated with individuals who exercised three times per week for 50 minutes in a routine that combined strength training, balance and flexibility training and cardiovascular training.


With age comes a decline in your metabolic rate. This is largely due to the reduction of muscle mass, decreasing the amount of calories you burn at rest as well as the amount of calories burnt through digestion and completely daily tasks. A study conducted by Hiroshima University in Japan found if older adults do not adjust their food intake in line with their decreasing energy requirements, they will accumulate fat, which in turn accelerates aging. This was supported in a recent 2019 study, that found that a calorie restricted diet helped to decrease inflammation and improves proteostasis (a hallmark of aging).


To avoid accumulating fat as you age, it is important to adjust your caloric intake. If you already experience overweight or obesity it is integral to focus your efforts on losing excess body fat to promote lifespan and longevity. The second hallmark of aging - telomere attrition - was closely linked to body weight. This is because overweight and obesity are characterized by excess adipose tissue and chronic inflammation, which in turn shorten and damage telomeres and aggravate the other hallmarks of aging, particularly deregulated nutrient sensing and stem cell exhaustion.


According to the epigenetic clock theory, for every ten point increase in body mass index (BMI), the biological human age is accelerated by 2.7 years. Living life at a healthy weight is integral to slow down the natural aging process, allowing you to live with a higher quality of life and for longer. So if you want to lose excess body weight, how can you do it? Alongside adjusting your caloric intake as mentioned, increasing your physical activity will also help to create an energy deficit, reducing inflammation and body fat.


When you exercise, metabolic adaptations occur that promote efficiency in the delivery of oxidized fatty acids during exercise. Individuals who are considered physically fit oxidize more fat and less carbohydrates during exercise, meaning that fat is metabolized more effectively as a fuel source. This happens because the body attempts to conserve muscle and liver glycogen stores, to maximize endurance and strength during a workout of any intensity. This is one of the reasons why fitter individuals are able to work out for longer than unfit individuals.


A clinical trial published in the Journal of Applied Physiology looked at fat metabolism in active men during a resistance training day compared to a control day. The researchers concluded that because resistance training improves body composition, particularly the increased capacity of the skeletal musculature, this enhances the efficacy of fat metabolism, even on non-training days. What this means in layman’s terms is that the more you exercise, the more efficient your body becomes at metabolizing and using energy. In relation to aging, this is associated in research with longevity, boosted mitochondrial function and ultimately delayed biological aging.


A study published by the International Journal of Geriatric Psychiatry evaluated the effects of exercise on the aging process in older adults. The randomized clinical trial found that endurance training for three hours per week was associated with a more stable cognitive status and less signs of aging, after just one year. As you age, neurodegenerative diseases like Alzheimer’s and Parkinson’s can be a real concern. Research has found that maintaining a consistent exercise routine is linked to a lower risk of developing these conditions. A randomized controlled trial conducted in five nursing homes with patients suffering with Alzheimer’s found that a targeted exercise program resulted in a slower decline. To support this, a systematic review published in 2008 concluded that exercise is integral to not only managing and slowing down cognitive decline but to also prevent it from occurring.


Aging is inevitable. Every moment you get older than you’ve ever been - there’s no slowing down the hands of time, so it’s best to focus on what you can control. What you can control is what you do on a daily basis: the food you eat, the exercise you do, the habits you engage in. Your daily decisions decide whether you’re going to have a long healthy life, or experience premature aging and rapid physical and cognitive decline. Regular exercise targets each of the nine hallmarks of aging, helping to slow down the inevitable to help you enjoy life to the fullest while you can.

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