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Biological vs chronological age: can lifestyle revert aging?

In her recent book True Age, pathology professor Morgan Levine makes the case to distinguish between two concepts of aging. We have a fixed age based on our birth, our chronological age, and a malleable, biological age, “which can be affected by our lifestyle choices.”

French writer Victor Hugo stated that our forties are the old age of youth, whereas our fifties are the youth of old age, but how much truth is there in our own perception of age?

Morgan Levine (who recently left the department of Pathology at Yale Unversity to join Altos Labs, a biotech company trying to slow down human aging) tries to convince us how the cutting-edge research on aging should make us think more seriously about lifestyle and not only about heredity.

“Nude Old Man in the Sun” (oil on canvas by Mariano Fortuny, 1871); Fortuny was influenced by the style of Jusepe de Ribera; click over the image to see it in detail with the Prado Museum’s multimedia tool

We tend to imagine that the genes inherited from our ancestors are the only real culprits of how heredity manifests. Still, this notion is mistaken since our body, its health, and the way it looks and ages is a dynamic system influenced by hundreds of thousands of genes, some of whom carry potential instructions from previous hominins but also other organisms such as bacteria, “and the environment in which those genes are acting makes all the difference to how we turn out,” explains Journalist Carl Zimmer, author of the 2018 book She Has Her Mother’s Laugh.

According to Zimmer, “we cannot understand the natural world with a simplistic notion of “genetic heredity,” and the popular notion of a correlation between genes and clearcut functions is a misconception: the Mendelian laws of inheritance are not just “exquisitely fragile” but “regularly broken.” Complex traits arise out of the combined action of hundreds of genes depending on the environment an individual grows up in.

Relativizing genetics’ importance in aging

To Morgan Levine, “only 10-30% of our lifespan is estimated to be due to genetics”:

“The wonderful thing, compared with chronological age, is that biological age is modifiable. We don’t yet know exactly how to modify it to the greatest extent, but the clock can be made to tick slower, or even possibly go backwards, in response to our behaviors (though it can also speed up). The first step is getting a valid and reliable measure of it, which my lab has been working on.”

The thesis is enticing: the younger our biological age versus our chronological age, the healthier the years ahead of us. Even if genetic predispositions or some accumulated negative environmental imprints over the years cannot be altered, we can influence our biological age with healthy choices and viable strategies anybody can reach. So far, the most significant barrier is access to knowledge on the matter:

“On average, people who rate younger biologically, compared to others their age, tend not to smoke, drink minimally, exercise regularly, eat more leafy greens, consume less red meat, get better sleep, and experience less stress.”

The impact of your behaviors and the environment

The field of epigenetics (her specialty) is no less than the “operating system of the cell,” dictating the primary function of each one of our cells: their metabolism, their instructions to divide, or their role depending on their “epigenome” or function instructions (despite sharing the same DNA sequence, neurons, and epidermal cells, for example, assume their instruction roles).

But the cells’ epigenome —the chemical compounds that instruct the genome what to do physically and functionally— don’t stay the same as we age, and the way these instructions change over time varies radically among people: our “true age,” that is, how old are we biologically, will depend on how porous are we to the environment (how are we affected by events, work, pollution, stress), and to the way we exercise, eat, or sleep.

Wim Hof, aka “The Iceman,” has grown his public figure around his ability to withstand low temperatures

Even though there is no universal way to assess our biological age, scientists have built scales that make a guess depending on scores regarding inflammation, liver functioning, and other predictors related to the “epigenetic clock.” This scientific guess is more precise than previous measure systems such as the length of the proteins protecting the extremities of the genes within one person’s cells (telomeres) or the metabolic age score, an equation proposed by a 1919 study by Harris and Benedict that reflects our fitness in comparison with our age.

Epigenetics studies have improved in the last years, and their models examining gene activity conclude that most people have a biological age that stays within five years of their chronological age. Can lifestyle, diet, and a better environment make us much younger than what our documents state?

Researchers like Morgan Levine are convinced about it (Levine helped develop Index, an epigenetic measure licensed by at least one company, Elysium Health, and was recruited in june 2022 by anti-aging biotech firm Altos Labs, backed by Jeff Bezos, among others).

DNA methylation regulates gene expression

Instead of waiting for science to find ways to increase our lifespan, tools such as epigenetics give decisive information about “slow aging,” no matter our chronological age. If the genome (the “ingredients” of our organism) remains the same, the epigenome (or the way the potential within the genes manifests) will change depending on factors such as lifestyle and age.

Our cells control gene expression through an epigenetic mechanism called DNA methylation, in which certain molecules turn “off” some gene activity, speeding aging in key parts of the organism. Scientists can match samples of cells with scores of DNA methylation and tell the relation between the biological and the chronological age of a person.

Some people’s “true age” is younger than it is in administrative terms, and in other cases, the phenomenon is the opposite: inflammation, chronic stress, chronic infection or immune challenges, poor sleep, poor diet, sedentarism, lack of relations, or suffering addictions are some of the factors that speed biological age versus our chronological one.

If it’s not only genetics but behavior, how can the way we live affect our odds? Studies establish the dilation between biological and chronological age in several years, but the most essential part of it, argues Morgan Levine, is how it can affect the quality of life in old age, to the point that:

“(…)if we could each slow our aging process down by seven years so that, at seventy, we had the biological profile of the average sixty-three-year-old, mortality risk from nearly every major disease would be cut in half.”

Avoiding “inflammaging”

Staying in good shape as much as possible can dramatically increase life expectancy at an advanced age, as some people remaining active at ever-increasing chronological ages already show. Even if our body’s gene expression changes over time, “how quickly or slowly our body diverges from its once youthful form is not predetermined,” states Levine:

“Things like damage and stress can accelerate it (…). When it comes to our bodies, every day we are alive, we encounter things that may shift our configurations: radiation, toxic chemicals, and damaging particulate matter.”

The link between chronic stress and accelerated aging is especially concerning as we enter an era of vanishing boundaries between work, personal life, and non-stop digital entertainment: studies show how chronic stress shortens the protective extremities of chromosomes (telomeres) in people’s cells, weakening the protection and abilities of genetic material to make specific molecules and proteins, self-repair and divide properly.

Ron Howard’s 1985 “Cocoon,” an American science fiction comedy-drama about the “fountain of youth”

Chronic stress can also beget inflammation and prevent the body from self-adjusting as a low-grade chronic swelling due to the overstimulation of our innate immune system. Consequently, the so-called “inflammaging” is the opposite of a healthy reaction of the organism to fight viral and bacterial infection through a temporary immune reaction or controlled systemic inflammation.

The human body’s ability to self-regulate lies in the evolutionary advantages accumulated in our relationship with environmental signals: our organisms are open systems that take resources not only for survival, preservation, and reproduction but also to feed repair mechanisms that react to our lifestyle choices.

Damage, stress, or pollution can shorten life expectancy and act as negative stressors, yet there are also positive ones. Chronic phenomena such as “inflammaging” can be prevented or even reverted through lifestyle strategies that take us out of our comfort zone: studies show how acute mild stressors, from exercise to caloric restriction, time-restricted eating or even “cold therapy/stress” (regular chilly showers or ice baths), benefit our metabolism and reinforce our cells’ epigenetics.

The importance of getting a bit uncomfortable

Regulated environments maintaining a constant temperature are detrimental to our immune response when facing either heat or frigid environments during short periods. When exposed to heat, our cells produce heat shock proteins, in response to perceived stressful conditions, countering infection and inflammation. In Scandinavia, the Baltic countries, or Japan, among other regions, traditional exposure to hot and cold environments for short periods have been a part of traditional leisure for centuries; now we know their benefits have a scientific base.

After a sauna, cold exposure triggers hormetic stress or the ideal level of exposure to stressors to trigger beneficial body reactions. Leaving the comfort zone in such a fashion has multiple benefits: an increase of the metabolic rate thanks to the activation of brown adipose tissue; increased fat burning and utilization; improved insulin sensitivity and glycemic control; reduced inflammation; improved mood; better sleep; increased alertness and focus; and enhanced stress tolerance.

There’s a caveat regarding acute mild stressors, explains Morgan Levine in True Age. If mild stress elicits beneficial responses in our immune system, very prolonged stress can have the opposite effect, “causing widespread damage and accelerating the rate of age-related decline.” Exercising too much, eating too little, or abusing bodily discomfort with activities such as cold therapy could be detrimental, whereas each person’s tolerance to mild stressors will have a different threshold, adding to the current confusion when it comes to guessing the tipping point between beneficial and detrimental strategies.

The accumulated evidence on the benefits lifestyle can have in our quality of life, and life expectancy should encourage anybody to follow suit, but we’re far from easily quantifying our “true age” and, once knowing our biological age, creating a personalized routine to maximize the long-term benefits of “slow aging.” Heterogeneity is too widespread to allow any person, group, or institution to generalize good practices because what may work and can be scientifically reproduced for one study population may not translate into other groups or cultures.

Strategies to reduce biological age

Exercise transforms our immune system but not in the way medicine had traditionally thought: exercise does not suppress the immune system; on the contrary, it reinforces it in the long term. A 2018 study published in Frontiers in Immunology confirms that exercise also benefits the immune system in the short term by boosting self-defenses against pathogens, reducing the risk of infections. Regular exercise is the best way to increase one’s “healthspain,” or the period of healthy aging in which we can live with no impediment, as opposed to age-associated disease and disability.

Though some generalizations can be backed with studies and self-reported experiments (“biohacking“): we know that the rate of biological aging is highly malleable, hence expressions like “looking young” or “looking old” for our age have a biological foundation that can be assessed. We also know that conscious actions regarding lifestyle, behavior, psychology, or the environment, will affect our biological age.

Asked about why “biological age” vs. “chronological age” is important, Morgan Levine argues that epigenetic aging (aging at the scale of cells) is a crucial predictor of life span and disease: when cells divide, they replicate their DNA, but this copy doesn’t happen all at once across the entire genome, with the regions most used by the cell replicating first and the regions that are turned off copied at the end. Studies show that both aging and cancer take advantage of the bigger odds of having altered patterns in the process of DNA copy in the “early” and “late” replicating regions.

Sean Connery and Christopher Lambert in the fantasy action-adventure film Highlander (1986), an apparently never-ending fight between immortal warriors

A weak replication introduces a bigger risk because the damage in regions that produce proteins and molecules helping prevent damage may block key response mechanisms activated by events such as environmental hazards, cellular or organ malfunction, etc. Biohacking speculates with the possibility of deeply “reprogramming” or “reset” our epigenome to prevent further deterioration. By mirroring a young epigenome thanks to environmental changes, could the instructions within our cells regain their prime?

“It is possible that cells that have acquired random errors simply “remember” their initial blueprint and can restore it when signaled to. Another possibility, however, is that the changes we observe in the epigenetic pattern are simply a response to something in the aging environment and that they can be turned off or reversed under the right conditions.”

Not only what you eat, but when

The rise of better ways of measuring how well our cells behave at the biochemical level (through the molecular process of methylation) could be the beginning of a new field of personalized aging, one in which fine-tuned aging profiles updated over time could serve as a blueprint to counter genetic and environmental fatalism with a proactive strategy to age “better,” and potentially live longer, remaining fully functional at very advanced chronological ages.

So far, the existing, proven mechanisms to slow down and potentially reverse the effects of the aging process in the body don’t depend on expensive, exclusive high-tech therapeutics but rather on old-school common sense: eating well, mostly leafy plants and not too much (as put by Michael Pollan a few years ago); exercise daily, sometimes beyond one’s own comfort zone; sleeping well and regularly; and introducing a few “acute mild stressors,” from shortening the amount of ours within a day in which we eat, to exposing our body to cold showers (or any other proven cold-exposure therapy). Explore and know one’s limits, so the combination doesn’t do too little not too much.

Not eating too much wouldn’t suffice, but eating healthily helps avoid injuries during and after exercise. More surprisingly, recent studies show that meal timing also matters, affecting our circadian rhythm, the quality of our sleep, or the resources our body needs to process meals. Experts such as Satchin Panda, a biologist specializing in circadian rhythms, relate time-restricted feeding (limiting our “feeding hours” during the day to 12 consecutive in total) to regulating appetite, gastrointestinal function, nutrient absorption, pancreatic insulin secretion, and liver (hepatic) enzyme activity.

Is there a “true” age? Or plain marketing spin?

A seminal review study published in the British Medical Journal involving 8,762 male participants over 2 decades found that “muscular strength is inversely and independently associated with death from all causes and cancer.” Muscular strength has also been associated with lifespan. A recent study among 4,449 participants over 50 years old found that death from all causes was 2.66 times higher in those with low muscle strength, and several studies have found a link between grip strength and healthy aging and longevity.

Shawn Wells mentions these studies in his practical book The Energy Formula, in which he reminds readers of the main benefits of resistance training: enhances muscle strength; helps reduce visceral fat; helps improve insulin sensitivity in dealing with carbohydrates; improves blood pressure; can increase bone mineral density (BMD); can protect against injuries; and improves cognition.

Was it common sense (or, as an alternative, “virtue” in the classical training prescribed in Classical times) all along?

If it all comes down to the equivalent of “virtue” in ancient Greece (a blend of moderation, physical exercise, and mental cultivation) plus a healthy diet similar to the Mediterranean with little meat, leafy greens, and healthy carbohydrates in modest intakes and within 12 hours (time-restricted), why packaging it into a marketable, expensive service if it could be a part of the future of personalized health, potentially affordable and so scalable it could aim at universality?