10 minutes

HIT & Biological Clocks

HIT & Biological Clocks
Justin Stebbing

Aging clocks and exercise latest today, but first I note that the annual carbon dioxide emissions generated by forest fires are now higher than those from burning fossil fuels in Japan, the world’s sixth-largest CO2. In particular, emissions from boreal-forest blazes, such as those in Canada this year, “showed a rapidly growing trend”, says a new report:

So, anyone eat too much recently. Well, a few lucky people find a fitness routine they love and stick to it. But many of us simply want to get our workout over with as quickly as possible. For those in the latter camp, it’s hard to resist headlines claiming we can get in shape in five minutes or less per day. Such a thing seems too good to be true, but an emerging body of research suggests these micro-workouts, a few 20 second rounds of stair-climbing, four-second sprints on an exercise bike, or two minutes of dashing to catch the bus — can improve fitness, prevent disease and extend one’s life. These activities are easier to slip into your schedule than the recommended 150 minutes of moderate weekly exercise (or 75, if you make it vigorous, by running, for instance). However, some scientists say such micro-workouts, also called exercise snacks, are oversold. And even those who tout their benefits say claims that they are as good as, or better than, more traditional workouts go too far.

The concept builds on more than 2 decades of research into HIIT, or high-intensity interval training. HIIT involves a series of nearly all-out efforts, usually 20 to 60 seconds long, interspersed with short rests, and then repeated again and again. Some studies suggest that HIIT workouts deliver many of the same benefits as steady, moderate-intensity exercise, including improved aerobic fitness and blood vessel function, in less time:

Not everyone agrees. Most lab studies of short-but-intense efforts are small, limiting their statistical power. Outside of the lab, wrist-worn activity monitors allow for studies of larger groups of people but may not  accurately capture factors like intensity, especially for short periods. Plus, while studies suggest that intense intervals are safe, even for people in cardiac rehab, strenuous exercise can, in some cases, raise the risk of sudden heart problems. Lastly, micro-workouts may not actually motivate people to exercise; research indicates time restraints aren’t actually the biggest barrier. A more significant one, is that many people don’t enjoy it, especially when they’re starting out. And intense workouts are often more unpleasant than moderate ones. The bottom line is intense bursts of effort for five minutes or less one or more times per day probably do provide some benefit, especially if you truly don’t have any other time to exercise or if you spend long stretches glued to your chair.

More research, currently underway, will determine the optimal “dose” — how many bursts you need, and how long and hard they should be, to produce meaningful changes in your health. However, decades of studies, with many thousands of participants, more clearly support the health benefits of racking up around 150 minutes of moderate activity, or 75 minutes of vigorous movement, per week. So what you shouldn’t do is replace another type of exercise habit, especially one you enjoy, with micro-workouts:

And in the age old debate of walking vs running, who wins? Walking is among the world’s most popular forms of exercise, and far and away the most favoured. And for good reason: it’s simple, accessible and effective. Taking regular walks lowers the risk of many health problems including anxiety, depression, diabetes and some cancers. But not too slowly, right:

However, once your body becomes accustomed to walking, you might want to pick up the pace, said Alyssa Olenick, an exercise physiologist. If you can nudge even part of your walk into a run, it offers many of the same physical and mental benefits in far less time. But just how much better is running? And how can you turn your walk into a run?

When considering the health benefits of an activity like walking or running, there are two connected factors to keep in mind. One is the workout’s effect on your fitness, that is, how it improves the efficiency of your heart and lungs. The second is the ultimate positive outcome: does it help you live a longer life?

The gold standard for assessing fitness is VO2 max, a measure of how much oxygen your body uses when you’re exercising vigorously. It’s also a strong predictor of life span. Even doing a small amount of activity, like taking slow steps throughout the day somewhat improves VO2 max compared with staying completely sedentary, according to a 2021 study of 2,000 middle-aged men and women. But bigger benefits come when you begin walking faster, which raises your heart and breathing rates.

If you’re working hard enough that you can still talk but not sing, you’ve crossed from light to moderate physical activity. Studies suggest that moderate activity strengthens your heart and creates new mitochondria, which produce fuel for your muscles. What makes running better? So how does running compare with walking? It’s more efficient, for one thing. Why? It’s more than the increased speed. Rather than lifting one foot at a time, running involves a series of bounds. This requires more force, energy and power than walking. For many people first starting out, running at any pace, even a slow jog, will make your heart and lungs work harder. That can raise your level of effort to what’s known as vigorous activity, meaning you’re breathing hard enough that you can speak only a few words at a time.

Guidelines recommend 150 minutes to 300 minutes per week of moderate-intensity aerobic activity, like brisk walking, or half as much for vigorous activity. That might suggest that running is twice as good as walking. But when it comes to the key outcome of longevity, some studies have found running to be even more effective than that.

In 2011, researchers asked more than 400,000 adults how much vigorous exercise (like jogging or running) and moderate exercise (like brisk walking) they did. They found that regular five-minute runs extended subjects’ life spans as much as going for 15-minute walks did. Regular 25-minute runs and 105-minute walks each resulted in about a 35 percent lower risk of dying during the following eight years:

Those numbers make sense, given running’s effect on fitness. Another study found that regular runners, including those jogging slower than 6 miles per hour, were 30% fitter than walkers and sedentary people. They also had a 30% lower risk of dying over the next 15 years:

Maybe we should be looking at walking and running as being on a continuum. The biggest benefit occurs when moving from none to a little exercise. Whether you’re walking or running, consistency matters most. But after that, adding at least some vigorous exercise to your routine will increase the benefits.

But, having said the above, here’s the dramatic reduction in type 2 diabetes risk with walking here, independent of the effect of walking on weight reduction. Speed matters. Compared with easy/casual walking (<3.2 km/hour), the relative risk of type 2 diabetes was 0.85 for average/normal walking (3.2–4.8 km/hour), but 0.61 for brisk/striding walking (>6.4 km/hour). Dose-response analysis suggested that the risk of type 2 diabetes decreased significantly at a walking speed of 4 km/h and above.

In related news, regular physical activity is associated with lower cancer incidence and mortality, as well as with a lower rate of tumour recurrence. The epidemiological evidence is supported by preclinical studies in animal models showing that regular exercise delays the progression of cancer, including highly aggressive malignancies. Although the mechanisms underlying the antitumorigenic effects of exercise remain to be defined, an improvement in cancer immunosurveillance is likely important, with different immune cell subtypes stimulated by exercise to infiltrate tumours. There is also evidence that immune cells from blood collected after an exercise bout could be used as adoptive cell therapy for cancer. A team now address the importance of muscular activity for maintaining a healthy immune system and discuss the effects of a single bout of exercise (that is, ‘acute’ exercise) and those of ‘regular’ exercise (that is, repeated bouts) on anticancer immunity, including tumour infiltrates:

How does dietary restriction enhance our immune response? Implicating the interplay between the gut microbiome and memory T cells in an experimental model. Nutrition affects all physiological processes, including those that regulate our immune system. While nutritional interventions demonstrate clinical potential, harnessing nutrition to precisely shape immune responses remains an ongoing challenge. Dietary restriction without undernutrition is a nutritional intervention shown to optimize general health, longevity, and immunity. Recently, a team proposed that dietary restriction-mediated optimisation of immunological memory requires synergism between the intestinal microbiota, memory T cells, and myeloid cells. These findings have major implications for the design of individually tailored nutritional intervention strategies aimed at preventing and treating disease. Further, the identification of defined microbes as determinants of immune responsiveness to nutritional interventions creates the opportunity to precisely modulate an individual’s microbiota to promote optimal therapeutic efficacy:

So how does this relate to aging. With each heartbeat of our ~2.5 billion, we are a little bit older, and what may seem paradoxical is true: the younger we are, the faster we grow old. At birth the heart beats about 140 times a minute. Even then it is already slowing down, and it continues to do so until the age of 25, when the rate levels off at about 70 beats a minute when the body is at rest. Yet the rate of beat is by no means the whole story, for how fast the blood flows is central, so that how much the heart pumps with each beat also comes into the picture. So, we find that the actual amount of blood pumped by the heart in a minute in 90-year-old person is only half as much as it was at the age of 20.

With all this, the inevitability of aging as a natural process has been challenged, although whether as the result of a cold objectivity or of unconscious desire for personal immortality on the part of the biologists concerned is a moot question. Longevity by itself, however, is not the only issue obviously. No one wants to decline in function inexorably.

So, it’s been said that an amoeba is immortal, barring accidents, taking amoeba as an example of single-celled organisms generally. This is a fallacy, for when an amoeba divides, two amoebas take the place of one, and the individuality of the original creature is lost. And most such cells die, from various causes, of which aging is certainly high on the list. The marvel is that a human being or any other creature consisting of many billion integrated cells can hold on to its total life and individuality so successfully. Some of the most vital cells in the body live individually only a very short time. Red blood cells, for instance, live but a few weeks and are continually replaced from a source within the bone marrow. The basal layer of cells of the skin continually proliferates and gives rise to the layers that constantly rub off. All the inner membranes of the body, such as the intestine and lungs, are forever being renewed in a similar way. Hair falls out of its follicles and is continually replaced (obviously not in me). And so it goes. Nerve cells, of the brain and elsewhere, stand somewhat apart, for there is no replacement, and in fact, no additions from infancy until death, which puts a high premium on conservation, although a process of renewal undoubtedly goes on within the confines of each such cell.

And, if you’ve ever been to a school reunion, you know that some people seem to age faster than others. Twenty-five years after graduation, one classmate can appear a decade younger than the rest, another a decade older. People know that intuitively but they don’t understand that it’s a biology that we’re trying to discover.

Scientists are working to quantify this phenomenon and put a number to a person’s “biological age” by looking at their cellular health instead of how many years they’ve been alive. Some of these measurements are now marketed as direct-to-consumer blood tests. But before you shell out hundreds of dollars to find out how old you really are, make sure you know what you’re paying for. Experts caution that while these tests are interesting in theory, and could be valuable research tools, they aren’t ready for prime time.

How do you measure biological age? Researchers define biological age as the accumulation of damage we can measure in our body. That damage comes from natural aging, as well as from our environment and behaviors.

The concept is often attributed to the British physician-scientist Dr Alex Comfort (perhaps better known for writing “The Joy of Sex”), who published a famous 1969 paper on the idea. But for decades, scientists didn’t know how they might measure someone’s biological age:

A major advance came in 2013 when Steve Horvath, a professor of human genetics proposed using a clock based on the emerging field of epigenetics. Over the course of our lives, our DNA accumulates molecular changes that turn on and off various genes. Dr. Horvath analysed these changes in thousands of people and developed an algorithm to determine how they correlate with age. At first he volunteered to participate in a study with his identical twin brother, Markus. The study was looking for epigenetic markers in saliva samples that might explain sexual orientation. (Steve is straight and Markus is gay.)  As a biostatistician, Horvath offered to analyse the results and found no link to sexual orientation. But he also looked for links between the volunteers’ age and epigenetic markers. “I fell off my chair, because the signal was huge for aging,” he says.

He found that patterns of methylation could predict a person’s age in years, although the estimates differed on average by around five years from each person’s chronological age. This was his paper:

Horvath has worked on aging clocks ever since. In 2013 he developed the eponymous Horvath clock, still among the best-known aging clocks today, which he calls a “pan-tissue” clock because it can estimate the age of pretty much any organ in the body. Horvath built the clock using methylation data from 8,000 samples representing 51 body tissues and cell types. With this data, he trained an algorithm to predict a person’s chronological age from a cell sample. Other groups have developed similar clocks, and hundreds exist today. But Horvath estimates that fewer than 10 are widely used in human studies, primarily to assess how diet, lifestyle, or supplements might affect aging:

These changes happen naturally as we get older; they can also be sped up by behaviors that affect health, like smoking and excessive alcohol consumption. As a result, estimates of biological age have been shown to be associated with things like life expectancy and health, he said. Several companies now sell tests for around $300 that use this technology to calculate your biological age by analysing your blood or saliva and comparing changes in your epigenome to population averages. But experts caution that epigenetic clocks can’t actually tell you much about your own health. That’s because they were designed to assess large groups of people, not individuals. Consequently, their results can be unreliable.

At a recent conference where Dr. Horvath spoke about the topic, an audience member said he had taken two different tests and received two different ages, 10 years apart. Dr. Horvath said that the man should have saved his money. “I think you could say the best of them are not completely useless,” said Daniel Belsky, an associate professor of epidemiology who developed his own epigenetic clock himself. “But these are not tried and tested clinical tools yet, so they’re more for the curious.”

Another problem with the tests is that it’s unclear what to do with the results. Scientists don’t know how to reverse someone’s biological age, or whether that’s even possible. In part, that’s why the epigenetic clocks were developed in the first place. Researchers hope to use them in clinical trials for anti-aging interventions to measure potential changes in the life spans of hundreds or thousands of people at a time. None of this has stopped companies from selling these tests alongside personalised health and lifestyle recommendations, in addition to supplements they say will roll back an individual’s biological age.

Epigenetic clocks aren’t the only products on the market promising to measure biological age. Some companies offer a panel of conventional blood tests you might receive at the doctor’s office, like cholesterol or hemoglobin A1C, a marker for diabetes. They say that because many of these numbers increase as we get older, they can be used as a proxy for a person’s biological age. For example, if you’re 45 but your cholesterol levels look more like the average 50-year-old’s, the test results might say your biological age is older than your 45 years.

Whether blood marker tests actually track biological age as opposed to general health is up for debate. But an advantage of this kind of test is that it measures factors that can be modified; we know how to lower blood sugar levels through medication and lifestyle changes, for example. In contrast, epigenetic age is currently more of a black box. Expanding access and using more frequent testing to optimize health seems fairly reasonable to me but any claims of accurate, individual-level determination of biological age should be approached with caution.

Whether the problem is to understand the process of aging, to do something about age, or to extend the natural limits of human life, the trouble is that we know too little about what is really going on. More than 3 centuries ago Francis Bacon examined the relationship between longevity, growth rate, and gestation period for a number of animals and concluded that there were too few facts on which to build a general theory of aging.

Since his time, mainly during the last 50 years, not only have facts mounted up but theories galore have been raised, only to be struck down or wither away. And no amount of information will serve if key facts remain missing, or if the factual mountain is so great that we lack ability to cull the trash. The cancer problem is comparable with this one, and possibly for much the same reason, after all age is the biggest cause of cancer, by a long mile. In both cases the answer lies in the nature and mutual relationship of living cells, now the subject of one of the most concerted attacks in the history of biological science.

One theory of aging, although it is more of a description than an explanation, has its roots in Aristotle, who saw life as the maintenance of a kind of internal heat or energy which had to be provided with fuel and could become exhausted, the heat of old age being a small feeble flame which could be extinguished by the slightest disturbance. This is fundamentally the same concept as that of the German embryologist C. S. Minot, who early in the 20th century described aging as development looked at from the other end; he saw senescence as a natural process inherent in the cell, resulting from the gradual loss of the energy stimulus originally present in the fertilised egg until none is left and the organism dies of old age. Although impugned by some biologists, this view of aging certainly calls attention to an overall waning process evident in all aging creatures and experienced by every human being who lives beyond the first flush of maturity.

What can happen when cell renewal or replacement suddenly comes to an end is seen all too clearly in those unlucky persons who have been accidentally exposed to large doses of radiation and could happen to much of mankind and other forms of life if nuclear war should ever be unleashed. Even a relatively mild exposure to neutrons shortens the life of mice and rats, and one theory of aging, sponsored more by physicists than others, is that aging results from the weak but continual radiation which reaches the tissues and cells of the body as cosmic rays from outer space, mainly from the sun, and from natural radiation from radioactive elements in the earth’s crust itself. When you’re a hammer, everything’s a nail, right? Cell death is as characteristic of the growing fetus within the womb as it is of middle age or later. What matters more, however, is how fast new cells can be made to repair the damage or make new tissue.

It's on this level of analysis that youth and age link hands. As long as new cells are born faster than old cells die, the body grows. When cell birth and cell death are in balance, body growth is no longer apparent, although the basic process of growth continues. When cell production lags behind cell destruction, things begin to happen, and we feel our age. Taste cells, for example, and probably those of smell, live each but a week or so and are continually replaced, yet the rate of replacement eventually fails to keep up with the loss. We all know gourmets require increasingly greater stimulation to satisfy their jaded senses.

All this is one of the great mysteries of life, at least to the biologist. Does the body age because its cells are aging and becoming fewer, or are the cells, so to speak, at the mercy of the body, or organism, as a whole?  Youth and age cannot be dissociated. The earlier search for the fountain of youth is the same as the present effort to postpone old age. The old long to regain youth, and the young wish to retain it. It may well be that the study of age and the aging process is a wrong emphasis and that the proper study of man should be youth, and that aging is merely its negation.

Right now, it’s too early to be able to assess the full impact on humans of the new potential therapies and drugs that are currently being investigated. We are still at an experimental stage, but we are getting closer. The main problem is that humans live a lot longer than worms, rats or flies. In addition, certain longevity therapies that have been successful in the case of mice cannot be tested directly on humans for ethical reasons. This shows an increase in longevity associated with caloric restriction and caloric restriction mimetic (CRM) drugs/treatments:

The combination of clinical trials on animals and epidemiological research on humans suggests that we are close to having drugs and therapies that can extend our healthspan by 10-15%. Caloric restriction and therapies that mimic the effects of caloric restriction on our metabolism are available and in some cases are touted as “longevity” drugs and supplements. However, we are far from being able to assess their real impact on longevity. How do you separate, for example, the effects of taking a daily dose of NAD+ from those of exercise and diet?

So, below are some examples of the most recent discoveries in the area of medical and pharmacological treatments for aging. Aside from hormonal therapies for those who need them, I am not sure that any of the drugs and supplements in this series have some chance of success but here’s the list as an fwiw:

  • Caloric Restriction. In all animal models, caloric restriction (CR), at the 20-30% level, extends lifespan. In humans, it has been difficult to keep people at a 20-30% caloric restriction for a long time, so we lack solid results.
  • Fasting is a much lighter version than CR and easier to implement. Fasting has shown significant positive effects in multiple areas: cardiovascular, diabetes and cancer.
  • Metformin is emerging as the most popular drug treatment of this list. Originally launched as a drug to treat diabetes, Metformin has shown protective effects against several age-related diseases in humans. Recently, a large clinical trial called TAME (Targeting Aging with Metformin) was launched across the U.S., covering 3,000 individuals between the ages of 65 and 79 for six years. We should see its results at the end of 2028.
  • Rapamycin is an mTOR inhibitor and one of the most promising “longevity” drugs. In animal models, rapamycin has been shown to extend the longevity of rats by 9-14% on average. There are a few ongoing trials and a few doctors have patients using it in small doses. However, there are some side effects and it requires close monitoring.
  • Hormone Therapy is another interesting area. Hormone therapy has been used successfully to stimulate and compensate the effect of aging, and there are a few inexpensive and effective therapies depending on the hormonal makeup of each individual. In this context, most hormonal therapies correct hormonal imbalances. This is probably the most advanced therapeutic area with enough clinical trials on humans supporting some preventive hormonal therapies.
  • Glycolytic Inhibitors have shown encouraging results in improving insulin sensitivity in dogs and rats and have extended the lifespan of rats. Glycolytic inhibitors have also been tested in the treatment of cancer by limiting the availability of glucose to cancer cells. So far research has been limited due to concerns on the toxicity of this drug.
  • NAD+ or Sirtuin Pathways Activators. Some of the most studied sirtuin activators are resveratrol and NAD+ (Nicotinamide Adenine Dinucleotide, a co-enzyme key to our metabolism). These have been shown to promote longevity in several species, but data on humans show limited or no effect. NAD+ precursors, compounds that can be synthesised into NAD+, are also being explored. There are more than 100 research studies in process in this area as we speak, but so far not one single study has been able to support the “longevity” claim used in its commercialisation.
  • Senolytics or Modifiers of the Senescence Process. Senescent cells accumulate during aging and secrete compounds that promote inflammation and cancer. Genetic and pharmacological strategies to target and kill senescent cells both enhance lifespan and improve health markers in mice with high levels of senescent cells. Human testing on potential pharmacological interventions combining several senolytic drugs have already been carried out, but we are still a few years away from identifying consistently effective therapies.
  • Spermidine is a key booster of autophagy and core substrate of any cell in our body. Spermidine in animal models is able to extend lifespan across flies, worms and mice. In humans, spermidine supplementation has also been correlated with lower blood pressure, improved immune response, improved cognitive parameters and lower inflammation. There are a few studies on humans that are currently being carried out and we expect to see results in the next 12-24 months.
  • SLGT2 Inhibitors and Acarbose. While research does not yet support any conclusion on the longevity effects of SLGT2i, or acarbose, several researchers have become interested in their potential to lower glucose and insulin peaks. The theory is that if we were able to reduce insulin spikes throughout the day, then we would improve insulin sensitivity, reduce IGF-1 and mimic some of the positive effects of caloric restriction. Mice studies strongly support this conclusion with lifespan expansions of 10%-plus for males.
  • Trehalose is a disaccharide that comprises two glucose molecules linked by a glycosidic bond. It is a nonreducing sugar that is not hydrolysed and does not interact with proteins or other molecules. Trehalose has attracted a lot of attention for its beneficial effects on animal models of neurodegenerative diseases and its potential ability to induce autophagy. However, we lack enough research to be able to assess its potential in helping extend healthspan in humans.
  • Stem Cells. Most of the research in stems cells has been focused on addressing diseases or structural (muscle, cartilage, bone) problems, in other words, repairing. However, as aging is characterised by a gradual decline in the ability of stems cells to regenerate and repair tissue and blood cells, the hypothesis is that injections of “induced pluripotent” cells or other type of “original” cells could counter the natural cellular decline and keep our body “young.” Their preventive use is still in its infancy but could be quite promising.
  • Reverse Thymic Involution. The potential to inhibit or slow down thymic involution is another interesting area in the field of longevity, even though proper human experiments are still a few years away. The thymus is the gland responsible for the production and maturation of T lymphocytes or T-cells, white blood cells that play a major role in our adaptive immune system. Thymic involution is a natural process that starts immediately after infancy and is one of the major factors driving immuno-senescence. There are a few therapies (e.g., bone
    marrow transplant or infusion of hematopoietic stem cells from a younger donor) that can be used to regenerate T-cells and B-cells to a much “younger” stage of their “life.”
  • Parabiosis consists of allowing older people to receive transfusions from younger and healthier individuals. While it works well for mice, the moral and ethical issues of applying the same treatment to humans are monumental, and we do not deem this a viable treatment.
  • Cellular Reprogramming. Fundamental to Yamanaka’s research are the aptly named Yamanaka factors (OCT4, SOX2, and KLF4), collectively known as OSK. These factors have shown that partial cellular reprogramming using the Yamanaka factors OSK can reverse age-related changes in vitro and in vivo. Median overall survival for wild mice treated with these 3 factors via injection was 109% longer. Human trials are probably five years away.

This long list suggests that we are now at a stage in the research on longevity and healthspan where, through a combination of diet, healthy behaviours (sleep, exercise, sun exposure, etc.), supplements, drugs and medical therapies, we have the potential to achieve a few key goals:

  • Prevent or at least delay the onset and progression of chronic diseases,
  • Slow down the rate of our biological aging,
  • Increase our healthspan and reduce the period of morbidity.

These are no small claims but are supported by a better understanding of how aging, the disease we are focused on, impacts our cells in every organ and tissue of our body. Others say eat broccoli which are packed with sulforaphane, a powerful sulphur-containing compound which activates pathways in the body that suppress inflammation, activate detoxification, and promote antioxidant action. Also get decent sleep but of course not too much! The body’s repair mechanisms occur while we sleep. One study examining the sleep habits of 1.3 million individuals found that those who slept between six to nine hours per night had the lowest risk of all-cause mortality compared to those who slept for less than six or more than nine hours per night. And finally here, reduce red meet intake which is associated with a greater risk of all-cause mortality and mortality from cardiovascular disease, the number one cause of death around those reading this. According to a decent study, swapping red meat for plant-based protein sources like beans or tofu is associated with a 13% lower risk of mortality in men and a 15% lower risk of mortality in women:

Clearly, we need to measure aging to study and understand it. But, age is much more than the number of birthdays you’ve clocked. Stress, sleep, and diet all influence how our organs cope with the wear and tear of everyday life. Factors like these might make you age faster or slower than people born on the same day. That means your biological age could be quite different from your chronological age, the number of years you’ve been alive.

Your biological age is likely a better reflection of your physical health and even your own mortality than your chronological age. But calculating it isn’t nearly as straightforward. Most aging clocks like the ones I mentioned above estimate a person’s biological age based on patterns of epigenetic markers, specifically, chemical tags called methyl groups that are layered onto DNA and affect how genes are expressed. The pattern of this methylation across thousands of sites on DNA seems to change as we age, although it’s not clear why. Some clocks promise to predict life span by estimating how a person’s body has aged, while others act more like a speedometer, tracking the pace of aging. Clocks have been developed for specific organs of the body, and for multiple animal species.

What can all these clocks tell us? It depends. Most clocks are designed to predict chronological age. But Morgan Levine at Yale says: “To me, that’s not the goal. We can ask someone how old they are.”  In 2018, Levine, Horvath, and their colleagues developed a clock based on nine biomarkers, including blood levels of glucose and white blood cells, as well as a person’s age in years. They used data collected from thousands of people in the US as part of a different study, which followed the participants for years. The resulting clock, called DNAm PhenoAge, is better at estimating biological age than clocks based solely on chronological age, says Levine. There are lots of these clocks now:

But, a one-year increase in what Levine calls “phenotypic” age, according to the clock, is associated with a 9% increase in death from any cause, as well as an increased risk of dying from cancer, diabetes, or heart disease. If your biological age is higher than your chronological age, it’s fair to assume you’re aging faster than average, says Levine.  But that might not be the case, says Belsky. He says there are many reasons why biological age might exceed a person’s years.

Another popular clock, also developed by Horvath and his colleagues, is called GrimAge, in a nod to the Grim Reaper. Horvath claims it’s the best at predicting mortality, and he’s been applying it to his own blood samples. His results were consistent with his chronological age two years ago, he says, but when he ran another test around six months ago, his GrimAge was four years older than his age in years. That doesn’t mean Horvath has shaved four years off his life span, “You cannot directly relate it to how long you’ll live,” he says, but he thinks it means he’s aging faster than he should be, though he’s still puzzled as to why.

Others have used changes in their results to infer that their rate of aging has slowed, usually after they started taking a supplement. But in many cases, the change can be explained by the fact that many epigenetic aging clocks are “noisy”, prone to random errors that distort their results.  The problem is that at each area of the body where methyl groups attach to DNA, very slight changes take place over time. These subtle changes can be magnified by errors in methylation estimates. It ends up being a huge problem, says Levine, and results can wind up being off by decades.  To answer this, they are “breaking apart existing clocks” and comparing them. They hope to work out what different clocks are measuring, and how to build better ones in the future:

That potential could lie in clinical health checks, says Horvath, where clocks could be used alongside tests of blood pressure and cholesterol to help people understand how fit and healthy they are, or whether they are at risk of disease.  “Epigenetic clocks will never replace clinical markers, [but] the clocks add value to them,” he says. “I think five years from now we will have human blood-based clocks that are so valuable that they could be used [clinically].” In the meantime, eating a healthy diet, avoiding smoking, and getting enough exercise remain some of the best ways to stave off the impacts of aging. We don’t need new aging clocks to prove that those strategies can help keep us well.

And ask an elderly person how old they are, even as a doctor asking a patient, and you won’t get a straight answer. Why do so many people have an immediate, intuitive grasp of this highly abstract concept of “subjective age,” when randomly presented with it? It’s bizarre if you think about it. Certainly most of us don’t believe ourselves to be shorter or taller than we actually are. We don’t think of ourselves as having smaller ears or longer noses or curlier hair. Most of us also know where our bodies are in space, what physiologists call ‘proprioception.’ Yet we seem to have an awfully rough go of locating ourselves in time. The gulf between how old we are and how old we believe ourselves to be can often be measured in light-years, or at least a goodly number of old-fashioned Earth ones.

As one might suspect, there are studies that examine this phenomenon. There’s a study for everything. As one might also suspect, most of them are pretty unimaginative. Many have their origins in the field of gerontology, designed primarily with an eye towards health outcomes, which means they ask participants how old they feel, which those participants generally take to mean how old do you feel physically, which then leads to the rather unsurprising conclusion that if you feel older, you probably are, in the sense that you’re aging faster.

But “How old do you feel?” is an altogether different question from “How old are you in your head?” The most inspired paper about subjective age asked this of its 1,470 participants, in a Danish population (Denmark being the kind of place where studies like these would happen), and what the two authors discovered is that adults over 40 perceive themselves to be, on average, ~20% younger than their actual age. “We ran this thing, and the data were gorgeous,” says David C. Rubin (75 in real life, 60 in his head), one of the paper’s authors and a psychology and neuroscience professor at Duke University. “It was just all these beautiful, smooth curves.”

Why we’re possessed of this urge to subtract is another matter. Rubin and his co-author Dorthe Berntsen, didn’t make it the focus of this particular paper, and the researchers who do often propose a crude, predictable answer, namely, that lots of people consider aging a catastrophe, which, while true, seems to tell only a fraction of the story. You could just as well make a different case: that viewing yourself as younger is a form of optimism, rather than denialism. It says that you envision many generative years ahead of you, that you will not be written off, that your future is not one long, dreary corridor of locked doors.

Rubin and Berntsen also made a second intriguing discovery in their work on subjective age: people younger than 25 mainly said they felt older than they are, not younger which, again, makes sense if you’ve had even a passing acquaintance with a 10-year-old, a teenager, a 21-year-old. They’re eager for more independence and to be taken more seriously; in their head, they’re ready for both, though their prefrontal cortex is basically a bunch of unripe bananas. In Rubin and Berntsen’s 2006 study, socioeconomic status, gender, and education did not significantly affect their data. One wonders if this has something to do with the fact that they conducted their research in Denmark, a country with substantially less income inequality and racial heterogeneity than many.

The picture changes when there’s more variety: a meta-­analysis of 294 papers examining subjective-­age data from across the globe found that the discrepancy between chronologic age and internal age was greatest in the USA, Western Europe and Australia while Asia had a smaller gap. Africa had the smallest, which could be read as an economic sign (poverty might play a role) but also a cultural one: Elders in collectivist societies are accorded more respect and have more extended-family support. “Could it be that feeling younger is actually dysfunctional and no longer helping you focus on what’s going on? That’s the more complicated question,” says Hans-Werner Wahl (69 in real life, 55 in his head), a co-author of the meta-analysis. “A lower subjective age may be predictive of better health. But there are other populations around the globe for whom it is not necessary to feel younger. And they’re not less healthy.”

If you mentally view yourself as younger, if you believe you have a few pivots left, you still see yourself as useful. Maybe. Margaret Atwood who like Freddie Mercury could be argued knew a thing or 2 about living wrote: “At 53 you worry about being old compared to younger people. At 83 you enjoy the moment, and time travel here and there in the past 8 decades. You don’t fret about seeming old, because hey, you really are old! You and your friends make old jokes. You have more fun than at 53, in some ways. Wait, you’ll see! :)”

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