As far as we know, the fountain of youth is boring

While we know more about health, aging, and longevity than ever before in human history, clear and concise guidelines for pursuing these outcomes remain elusive. Over the last decade or two, the industry built around longevity and anti-aging strategies has grown immensely, which has muddied the waters; for every actionable and evidence-based recommendation for lifespan or healthspan extension, there are countless overhyped “biohacks” that lack evidentiary support. As such, the purpose of this Research Spotlight is to cut through the noise and identify some evidence-based strategies to support successful aging.

To begin, let’s focus on a new study by Spartano and colleagues (1). The purpose of this study was “to identify whether physical activity and sedentary time, measured objectively with accelerometry, were associated with… predicted epigenetic age models in blood samples.” In the study, they explored associations using three different epigenetic age models: Hannum, Horvath, and GrimAge. Generally speaking, these types of models (also known as “epigenetic clocks”) aim to use DNA methylation patterns in order to predict an individual’s biological age, which may not necessarily be the same as their chronological age. For example, someone who was born 35 years ago has a chronological age of 35, but might have a biological age of 41 if they frequently engage in behaviors that accelerate biological aging. In this Research Brief, I’ll exclusively focus on the GrimAge data; GrimAge is a second-generation epigenetic clock that builds upon the prior generation by incorporating additional predictive data, and GrimAge appears to outperform other epigenetic clocks when it comes to predicting aging-related clinical outcomes and mortality (2).

In order to explore the relationships between these variables, the researchers utilized data from the Framingham Heart Study, which is a large, multigenerational, longitudinal study that started in 1948. The first cohort of participants participated in the study beginning in 1948, the children of the first cohort (the second generation) began the study in 1971, and the third generation of participants began in 2002. The present study utilized data from two data sets: the “Third Generation Exam 2” and “Offspring [second generation] Exam 9.” Physical activity was assessed via accelerometer data (with accelerometers worn for a period of 3-8 days), and blood samples were drawn to obtain DNA methylation data. The primary outcome of interest was “epigenetic-predicted age residuals,” which essentially describes the gap between biological age (based on the GrimAge model) and chronological age. After excluding participants with insufficient data for analysis, the researchers were left with data from a total of 2,435 subjects.

A very concise summary of the key results is presented in Table 1. In short, physical activity level (expressed as steps per day or the amount of moderate-to-vigorous intensity physical activity) was inversely associated with epigenetic-predicted age, whereas sedentary time was positively associated with epigenetic-predicted age. The strength of these relationships was attenuated, but not eliminated, after controlling for BMI. The authors further described these results in more tangible terms: “Walking 1500 more steps/day or spending 3 fewer hours sedentary was associated with >10 months lower GrimAge biological age… Every 5 min/day more [moderate-to-vigorous intensity physical activity] was associated with 19-79 days lower GrimAge.” In short, more physical activity and less sedentary time was associated with a delayed rate of biological aging; lower BMI contributed to this association, but didn’t explain the entirety of the relationship.

I wanted to cover this study in a Research Spotlight because I’ve been getting more and more questions about aging and longevity lately. Unfortunately, those questions are almost always about fad diets or dietary supplements. There’s a growing industry that seems to be preying on the concerns of a demographic known as the “worried well” – in this context, the term describes generally healthy individuals who are preoccupied with health optimization that aims to extend lifespan and delay or attenuate biological aging. This area is ripe for biohacker-types to roll in, whip up some interest in very speculative mechanisms, then put it all together with a nice nutrition-focused book that leads readers toward a lineup of supplements. In terms of implementation, it just might be the perfect grift (if you’re not afflicted by the burden of a conscience) – you encourage worried people to lean into their pre-existing concerns and amplify them, the worried people become life-long customers with no tangible, objective metrics to assess whether or not the interventions are working, and by the time they’re dying, they might start to figure out if the whole thing was worth it or not.

Fortunately I don’t need to rant about the problematic state of the life extension and anti-aging industry, because an open-access paper already did it (3). In an excellent review of a very popular book about lifespan extension and attenuation of biological aging, Dr. Charles Brenner describes the rampant speculation and misinformation fueling the rapid growth of the longevity-focused industry and online communities. I encourage people to read the entire article if they’re interested in this topic, but a few key excerpts summarize the review nicely:

• “To say that aging is a disease is to pathologize life itself.”
• “Lifestyle changes that improve fitness improve people’s health trajectory such that a person can go from an aging-worse lifestyle to an aging-better lifestyle. Getting healthier is not age reversal though.”
• “On social media, longevity followers appear to include a significant proportion of young adults, suggesting that anti-aging fad diets, drugs and practices are being adopted in ways that could add many years of exposure to drugs that lack an evidentiary basis for their off-label adoption.”
• “The book has popularized a stack of drugs and supplements with significant potential to harm the general public.”
• “The most important things that people can do to age better are to maintain high physical and mental activity.”

So, with that out of the way, what do we do about aging?

First and foremost, we need to approach it with a healthy perspective. As noted previously, we shouldn’t frame life itself as a pathology. Aging is a natural part of the process we call living; it is inevitable, and to live in fear of aging is to unnecessarily reduce one’s quality of life without any tangible benefit. In my opinion, the goal should not be to halt, reverse, or avoid aging, but rather to age successfully. In this context, “successful aging” involves extending one’s lifespan and healthspan, such that the individual retains a high level of physical, cognitive, and emotional wellness into their later years. In other words, the goal isn’t solely to increase the gap between the two numbers on your gravestone, but to simultaneously maximize the “area under the curve” when it comes to physical, cognitive, and emotional wellbeing. So, the bad news is that we currently don’t have the tools necessary to stop aging, and I doubt we’ll obtain them in our lifetimes. However, the good news is that we absolutely can take proactive steps to facilitate successful aging and support physical, cognitive, and emotional wellbeing. The even better news is that most fitness enthusiasts are already taking many of these steps in pursuit of their fitness goals.

A 2018 paper by Li and colleagues (4) explored the impact of adopting five different low-risk lifestyle factors: never smoking, staying in the “normal” BMI range (18.5–24.9 kg/m2), getting at least 30 minutes of moderate-to-vigorous intensity physical activity per day, moderate alcohol intake (5-15 g/day for females and 5-30 g/day for males), and a high diet quality score. Diet score was quantified using the Alternate Healthy Eating Index score, and “high quality” was operationally defined as being in the 60th percentile or higher. Compared to people who adopted zero of these low-risk behaviors, people who adopted all five had a projected life expectancy that was about 13 years longer (14.0 for females and 12.2 for males). If you’re looking for a basic “starter pack” for increasing lifespan and healthspan, these five behaviors are a very feasible starting point.

When it comes to lifespan extension or anti-aging effects, some of the more promising interventions across several different non-human species involve caloric restriction (5) and protein restriction (6). Naturally, this catches the eye of lifting enthusiasts who are hypervigilant about eating enough calories and protein to support muscle growth and maintenance, and causes them to wonder if they need to pick between their lifting goals and their longevity goals. By my read of the literature, the answer is no. 

First, I don’t view caloric restriction to be a particularly feasible intervention for most humans. Attempting to mimic experimental models of caloric restriction would involve starting at a comfortable energy intake that supports weight stability, then slashing it by 30-40%, and continuing it forever (7). One might hope that it gets easier over time, but that doesn’t appear to be the case; we certainly don’t catch glimpses of that effect in long-term weight loss studies, and animal studies seem to indicate that hunger does not diminish over time in these types of interventions (5). 

Second, I don’t think the juice is worth the squeeze when it comes to aggressive energy restriction. The benefits of caloric restriction are dependent on the severity of restriction, and the age at which restriction begins (the longer you wait, the less effective it is; the more aggressive you are, the less feasible and tolerable it is). Speakman and Hambly (5) estimate that starting a 30% energy restriction intervention at age 48 would increase human lifespan by only 2.8 years – 2.8 hungry, lethargic years, that is. It’s also worth noting that a caloric restriction intervention that is aggressive enough to extend lifespan would probably have some downsides that directly threaten health and survival, such as impaired immune function and wound healing (7). In other words, you might be increasing your predicted lifespan from a metabolic perspective, but you might be increasing vulnerability to acute causes of premature death. If our goal is to meaningfully extend lifespan and actually enjoy the years we’re gaining, that doesn’t seem like a viable path forward.

Third, the effects of protein restriction in non-human experimental models probably don’t generalize to humans. As reviewed by Speakman and colleagues (6), protein restriction seems to meaningfully and reliably extend lifespan in insects, but this doesn’t seem to generalize very well to rodent models. In rodents, caloric restriction is similarly effective when protein is or is not restricted simultaneously. Protein restriction does appear to independently increase lifespan in rodents, but the effect is very small and occurs in the context of restriction that is too aggressive to consider feasible or advisable. For example, Speakman and colleagues (6) estimate that reducing protein intake from 20% of energy to 4% of energy would increase lifespan by half as much as the typical caloric restriction intervention (without protein restriction). Furthermore, attenuation of sarcopenia (the age-related loss of muscle mass and function) is a key focal point of successful aging strategies. As muscle mass and function are lost, aging individuals lose the ability to safely and effectively complete activities of daily living, and susceptibility to falls and fractures becomes a very direct threat to health and longevity. In other words, some of the most pertinent concerns of aging individuals relate to loss of independence and fracture susceptibility, so the idea of promoting aggressive protein restriction in old age is a non-starter that represents yet another scenario where any theoretical metabolic advantage would be totally offset by vulnerability to other, non-metabolic risks that could acutely cause premature death or dysfunction. 

Finally, I’ll note that energy balance is continuous, not dichotomous. People are not “calorically restricted” or “non-calorically restricted,” but rather fall on a spectrum ranging from very low energy intake to a large abundance of energy intake. In terms of longevity, it seems that undernutrition (in terms of energy intake, not essential nutrient adequacy) is advantageous when compared to overnutrition, and studies linking low BMI to extended lifespan are probably picking up on that relationship. However, energy intake is coordinated by several interrelated brain systems, and aggressive, long-term caloric restriction (or trying to maintain an uncomfortably low body-fat percentage below one’s lower intervention point) can lead to prolonged discomfort. If your goal is to simply accumulate years, it would be advisable to maintain the lowest BMI possible without accelerating sarcopenia or impairing basic body functions (such as wound healing or immune responses). However, if your goal is to actually enjoy the years, the goal should be to adopt a set of habits and behaviors related to diet and exercise that facilitate a high activity level and the leanest physique you can maintain without meaningfully detracting from quality of life. For some individuals, losing body fat or maintaining a lean physique is exceedingly difficult. Fortunately, exercise and physical activity confer a wide range of cardiometabolic benefits that support longevity, even in the absence of weight loss or leanness (8).

If you remember from several paragraphs ago, I mentioned that I’d be discussing “proactive steps to facilitate successful aging and support physical, cognitive, and emotional wellbeing.” So far, we’ve been focusing a lot on the physical part, but cognitive and emotional wellbeing are critical to successful aging. For starters, it’s very convenient for fitness enthusiasts that exercise and physical activity have cognitive benefits that facilitate more successful aging of the brain. Exercise also facilitates better sleep patterns (8), which is not only good for the brain, but also associated with “longer healthy and chronic disease-free lifespan” (i.e., a longer healthspan) according to research by Stenholm and colleagues (9). However, evidence suggests (10) that an ideal approach for maintenance of cognitive function in old age is to utilize a combination of physical activity and cognitively engaging activities (in other words, engaging in a variety of activities that collectively challenge both the body and mind, in order to keep both of them sharp). There are also social and emotional elements that play into successful aging; research has indicated that loneliness is an independent risk factor for mortality (11), and that having a sense of “purpose” in life is associated with greater longevity (12). 

While scientists are hard at work figuring out the molecular mechanisms that accelerate aging, we need not helplessly wait for a miracle supplement to hit the shelves – we already have a pretty good blueprint for aging successfully. Don’t smoke, don’t drink excessive amounts of alcohol, and try to sleep well. Find some types of exercise and physical activity that you enjoy, and enjoy them regularly. Do things that stimulate your mind, form meaningful connections to people in your life, and live with purpose – not just to stave off dementia or add a couple years to your lifespan, but to enjoy life more fully. Eat enough to nourish your body and accommodate your hunger and satiety cues, but try not to overeat on a regular basis. Do some weight-bearing exercise (and ideally some resistance training) to attenuate and slow the impacts of sarcopenia – this will directly reduce some pertinent health risks, but will also preserve one’s independence and sense of purpose.

Earlier in this brief, I painted the life extension and anti-aging industry (and related online communities) with a broad brush, and portrayed them in a pretty negative light. This might make it seem like I’m disinterested in aging or longevity, but that’s really not true – I find the physiology to be fascinating, and maximizing the “area under the curve” for physical, cognitive, and emotional wellbeing is a top priority in my life. My distaste for this niche within the health and fitness world pertains solely to the actors that are currently running the show, and the highly speculative focal points that are currently at the center of attention. This current state of affairs is profoundly unproductive – fearmongers using mechanistically elaborate but unsubstantiated claims to push worried people toward ineffective or insufficiently researched supplement stacks, fad diets, and other “biohacks,” all while reinforcing a mental fixation on avoiding the inherently unavoidable. I can’t help but wonder if the stress, panic, and dread associated with this approach are defeating the purpose entirely. Over the next 10-15 years, I’m sure we’ll be presented with a few more supplements that are touted as the next “fountain of youth,” and none of them will come close to outperforming basic health-promoting strategies that extend one’s lifespan and healthspan. In reality, the closest thing we have to a foundation of youth is very boring, but very effective – a simple selection of habits and behaviors that support physical, cognitive, and emotional wellbeing. With that in mind, I hope more people will embrace the joyful process of successful aging, rather than clinging to fear-driven hopes to prevent aging altogether.

Note: This article was published in partnership with MASS Research Review. Full versions of Research Spotlight breakdowns are originally published in MASS Research Review. Subscribe to MASS to get a monthly publication with breakdowns of recent exercise and nutrition studies.

References

1.   Spartano NL, Wang R, Yang Q, Chernofsky A, Murabito JM, Vasan RS, et al. Association of Accelerometer-measured Physical Activity and Sedentary Time with Epigenetic Markers of Aging. Med Sci Sports Exerc. 2022 Sep 13; ePub ahead of print.
2.   McCrory C, Fiorito G, Hernandez B, Polidoro S, O’Halloran AM, Hever A, et al. GrimAge Outperforms Other Epigenetic Clocks in the Prediction of Age-Related Clinical Phenotypes and All-Cause Mortality. J Gerontol A Biol Sci Med Sci. 2021 Apr 30;76(5):741–9.
3.   Brenner C. A Science-Based Review Of The World’s Best-Selling Book On Aging. Arch Gerontol Geriatr. 2023 Jan 1;104:104825.
4.   Li Y, Pan A, Wang DD, Liu X, Dhana K, Franco OH, et al. The Impact of Healthy Lifestyle Factors on Life Expectancies in the US population. Circulation. 2018 Jul 24;138(4):345–55.
5.   Speakman JR, Hambly C. Starving For Life: What Animal Studies Can And Cannot Tell Us About The Use Of Caloric Restriction To Prolong Human Lifespan. J Nutr. 2007 Apr;137(4):1078–86.
6.   Speakman JR, Mitchell SE, Mazidi M. Calories Or Protein? The Effect Of Dietary Restriction On Lifespan In Rodents Is Explained By Calories Alone. Exp Gerontol. 2016 Dec 15;86:28–38.
7.   Speakman JR. Why Does Caloric Restriction Increase Life And Healthspan? The ‘Clean Cupboards’ Hypothesis. Natl Sci Rev. 2020 Jul 1;7(7):1153–6.
8.   Gremeaux V, Gayda M, Lepers R, Sosner P, Juneau M, Nigam A. Exercise And Longevity. Maturitas. 2012 Dec;73(4):312–7.
9.   Stenholm S, Head J, Kivimäki M, Magnusson Hanson LL, Pentti J, Rod NH, et al. Sleep Duration and Sleep Disturbances as Predictors of Healthy and Chronic Disease-Free Life Expectancy Between Ages 50 and 75: A Pooled Analysis of Three Cohorts. J Gerontol A Biol Sci Med Sci. 2019 Jan 16;74(2):204–10.
10.   Gavelin HM, Dong C, Minkov R, Bahar-Fuchs A, Ellis KA, Lautenschlager NT, et al. Combined Physical And Cognitive Training For Older Adults With And Without Cognitive Impairment: A Systematic Review And Network Meta-Analysis Of Randomized Controlled Trials. Ageing Res Rev. 2021 Mar;66:101232.
11.   Rico-Uribe LA, Caballero FF, Martín-María N, Cabello M, Ayuso-Mateos JL, Miret M. Association Of Loneliness With All-Cause Mortality: A Meta-Analysis. PLoS ONE. 2018 Jan 4;13(1):e0190033.
12.   Hill PL, Turiano NA. Purpose In Life As A Predictor Of Mortality Across Adulthood. Psychol Sci. 2014 Jul;25(7):1482–6.