Can we find therapeutics that mimic the benefits of a healthy lifestyle?

Finding ways to slow or reverse the aging process is big business. At the extreme end is tech entrepreneur Bryan Johnson, who sticks to a 1,900-calorie-a-day, no-sugar diet, daily exercise, and a strict 8–9 h of sleep a night. Johnson has also set up a data-driven longevity program called Blueprint that uses experimental interventions to attempt to minimize biological aging. Other tech billionaires are looking for quicker fixes to stave off the inevitable. They are sinking huge amounts of money into longevity research through founding or investing in longevity start-ups or funding basic research.

Of course, we already know that the best intervention to slow the degeneration that accompanies aging is a healthy lifestyle: most importantly, eating well and not too much, exercising, and getting enough sleep.

But not everybody is able to maintain healthy habits. So scientists are now asking, If they could understand how diet, exercise, and sleep slow the negative effects of aging, could they find therapeutic solutions that mimic the effects of these habits? Could we get the benefits of these “virtuous behaviors” without the sacrifices?

The skinny on caloric restriction

“To date, caloric restriction is the only intervention that is proven to extend lifespan across models, including humans,” says Maria Ermolaeva, a biochemist and longevity expert at the Leibniz Institute on Ageing–Fritz Lipmann Institute. For example, Ermolaeva cites a 2017 study that found that monkeys fed a reduced-calorie diet lived longer and had fewer age-related diseases than monkeys fed a normal intake. The 2019 CALERIE trial (Lancet Diabetes Endocrinol. 2019, DOI: 10.1016/S22138587(19)30151-2) showed that over 2 years, reducing calorie intake by 25% significantly reduced multiple cardiometabolic risk factors in healthy adults.

How restricting calories keeps us healthy longer is still being studied.

Caloric restriction stimulates autophagy—the process by which cells break down and recycle proteins. “That is a major protective pathway that converts the garbage of the cell into building blocks for new good things,” Ermolaeva says.

Among the evidence linking caloric restriction to autophagy is a study of human volunteers who followed a zero-calorie diet for 4 consecutive days and showed a significant increase in autophagy markers in their white blood cells after that time (Autophagy 2017, DOI: 10.1080/15548627.2016.1271513). And when the genes responsible for autophagy are knocked out in the worm Caenorhabditis elegans, the lifespan extension normally seen with caloric restriction is wiped out (PLOS Genet. 2008, DOI: 10.1371/journal.pgen.0040024).

A crucial piece of the puzzle is how autophagy impacts mitochondria, the energy-generating organelles within cells. One theory is that limiting nutrients causes cells to remodel the way they generate energy. Mitochondria exist in two interchangeable forms: as single organelles, known as the fragmented state, or as a network, known as the torque state. Under normal conditions, they fluctuate between these states in response to changes in the cellular environment. Oxidative stress, for example, shifts the balance toward the fragmented state, which allows the cell to get rid of damaged mitochondrial units. When nutrients in a cell are scarce, mitochondria tend to switch to the torque state, which is a more efficient way to produce energy, Ermolaeva explains. This state also starts to stimulate new mitochondrial formation and leads to other positive effects, including reducing the lipid content in the liver through metabolizing fat, which in turn reduces chronic inflammation and slows tissue degeneration.

Few people are willing or able to permanently live on a calorie-restricted diet, even given the clear benefits. One molecule that seems to mimic this process is the commonly used diabetes drug metformin. Ermolaeva says the drug “achieves comparable systemic effect by blocking mitochondrial respiration.” This biological stress leads to a similar remodeling of the mitochondria as the remodeling seen with caloric restriction. But trials in which researchers fed mice 0.1 g of metformin per 100 g of food in their diet have so far not produced a replicable lifespan extension (Aging Cell 2016, DOI: 10.1111/acel.12496). Recruitment for a 6-year human trial, called TAME (Targeting Aging with Metformin), has just started.

Ermolaeva says she has found another intervention that causes similar mitochondrial remodeling. Administering ultraviolet B (UVB) light through the skin of C. elegans provided resilience to age-related stresses, Ermolaeva and her team found. “It was a complete accidental discovery,” she says. Her group exposed worm larvae to UVB and then gave them several stress tests, including exposure to elevated temperatures. In worms that survived longer, the researchers analyzed proteomic data and found a link to the expression of genes related to new mitochondrion formation.

The team has also confirmed its results in human skin cells and mice by looking at markers for metabolic function. “The mitochondrial response is only in the skin, but the systemic effects are comparable to [a calorie-restricted] diet,” Ermolaeva says. That study is now published as a preprint before peer review (bioRxiv 2024, DOI: 10.1101/2024.03.05.583543).

Ermolaeva has concluded that UVB light disrupts the efficient fused mitochondrial networks in cells, because the UVB light sets off signaling similar to that caused by mitochondrial damage, although no actual damage is caused. “As a result, mitochondria become rapidly fragmented upon UV treatment, and this state lasts for several hours, leading to a drop in energy production that is perceived by the organism as nutrient stress,” Ermolaeva says. Even though the mitochondrial network recovers to its prior state within 36–48 h, the temporary change triggers a response that resembles caloric restriction.

“The only difference is that caloric restriction requires a long time and compliance,” Ermolaeva says. But in mice, UVB light achieved “the same effect as 30 days of diet in just 12 h with a single treatment on 30% of the skin surface of the animal.”

Now that Ermolaeva has proof of concept, she is trying to establish human trials. She thinks UVB light could be administered as a weekly phototherapy treatment, similar to treatments routinely offered to treat inflammatory skin diseases like eczema and psoriasis. UVB treatment might also sidestep some of the toxicity and side effects that drugs often produce.

Effortless exercise via a drug

You might not enjoy exercise, but epidemiological evidence shows that people who exercise live longer. A 2024 study tracking over 115,000 adults over 30 years showed that those undertaking two to four times the currently recommended amount of moderate or vigorous physical activity per week have a significantly reduced risk of mortality from all causes: a reduction of 21–23% for greater vigorous physical activity and 26–31% for greater moderate physical activity each week (Circulation 2022, DOI: 10.1161/CIRCULATIONAHA.121.05816). Again, the ability to adapt to external stress leads to long-term benefits.

But is it possible to stay on the couch and get the benefits with a drug?

Several groups are developing strategies focused on how exercise changes skeletal and heart muscles. “Muscles are probably close to 40% of the whole human body mass and a major site for burning calories,” says chemist Bahaa Elgendy from WashU Medicine, the medical school of Washington University in St. Louis, who is developing an exercise mimetic. Researchers are still investigating the origins of the longevity benefit, but the benefit could be linked to the improved glycemic control afforded by the type of muscle fiber, called “fast twitch” muscle, that exercise produces.

The molecule that Elgendy is working on is based on estrogen receptor–related receptors (ERRs), which are ligand-activated transcription factors. These proteins regulate gene expression by binding to a ligand that will then bind to DNA. Of three receptor subgroups, ERRα is highly expressed in high-energy-demand tissues, including skeletal muscle. In response to exercise, ERRα activates a range of genes controlling enzymes and regulatory proteins that make up energy production pathways, including those pathways that are also stimulated by caloric restriction to produce new mitochondria.

Elgendy and his collaborators have found that if ERRα is inhibited, either genetically or pharmacologically, animals experience a huge reduction in muscle mass and a reduced ability to create new mitochondria. “They are weaker, and they don’t have any appreciable level of endurance,” Elgendy says. “If we can activate these receptors, this would most likely have a similar beneficial effect [to exercise].”

With colleagues from WashU, Elgendy has started exploring this activation with a molecular probe, SLU-PP-332, that induces ERRα. When given the compound for 28 days, mice produced more fast-twitch muscle fibers that gave them enhanced exercise endurance—they essentially activated the same cellular reprogramming that occurs with exercise (ACS Chem. Biol. 2023, DOI: 10.1021/acschembio.2c00720). “It’s like you’re convincing the body that it’s running for a marathon,” Elgendy says.

Using those data, the team developed an ERRα-targeting small-molecule exercise mimetic with better drug-like properties and 50-fold more potency. Elgendy has cofounded a company, Pelagos Pharmaceuticals, to continue the work.

Another exercise-mimetic target is also related to mitochondrial health. At the University of Basel, Christoph Handschin, a biochemist specializing in skeletal-muscle-cell plasticity, is interested in the exercise-triggered protein PGC-1α.

Handschin started studying PGC-1α in mice, and, as anyone who has had a mouse as a pet will tell you, “These animals really like to run,” Handschin says. “We just give them running wheels,” and some can run 10 km in a night.

“Where you ramp up energetic demand, you also then induce PGC-1α gene expression,” he says. The effect is an increase in the number and quality of mitochondria (Proc. Natl. Acad. Sci. U.S.A. 2023, DOI: 10.1073/pnas.2302360120). Handschin thinks the PGC-1α protein is a master regulator of mitochondrial formation, and one way this role could be exploited to create an exercise-mimetic drug is through myokines, a class of hormones released by skeletal muscle cells. One myokine, irisin, a peptide with 112–120 amino acids, is known to promote fat metabolism (Nature 2012, DOI: 10.1038/nature10777). “It’s also regulated by PGC-1α and skeletal muscle, so it goes up in the context of exercise,” Handschin says.

Current studies are preclinical, but Handschin says that if irisin behaves in a similar way in humans, it could rapidly be developed as an exercise mimetic.

Mimicking sleep by inhibiting a protein complex

The third lifestyle factor thought to promote good health is sleep. Sleeping for fewer than 5 h per night is associated with increased risks of age-related conditions like type 2 diabetes and coronary heart disease (Sleep 2015, DOI: 10.5665/sleep.4886). Although the epidemiologic data are convincing, the molecular pathways accounting for the link are still poorly understood.

Ermolaeva thinks she has discovered the key to the benefits of sleep—through the aptly named dimerization partner, RB-like, E2F, and multi-vulval class B, or DREAM, complex. The protein complex regulates the way chromatin is packed in chromosomes. Changing chromatin compaction allows control of gene transcription, and the DREAM complex has previously been linked to preventing transcription in dormant cells.

But Ermolaeva’s study, currently published as a preprint before peer review, has uncovered the complex’s role in sleep (bioRxiv 2025, DOI: 10.1101/2024.06.26.600859).

Using C. elegans and mice with genetically disrupted circadian clocks that left them unable to sleep, Ermolaeva discovered that during wakefulness, the DREAM complex forms and keeps chromatin closed in a “protective state” to shield DNA from damage. But during sleep, DREAM activity goes down, allowing the chromatin to unravel so that DNA can be repaired.

When an animal’s sleep is disrupted, DREAM activity remains high, which means the chromatin stays in the closed state, stopping the DNA repair that normally goes on during sleep. Over time, this lack of repair leads to deterioration of normal cellular function.

Ermolaeva also discovered that pharmacological inhibition of the DREAM complex can reverse the negative impacts of a lack of sleep. “If we give DREAM inhibitors [to mice], there is 100% recovery despite sleep disruption still being in place,” she says. “We can mimic the benefits of sleep in a situation when sleep itself is not possible.”

Ermolaeva has identified the alkaloid harmine, also known as 7-methoxy-1-methyl-β-carboline, as a DREAM inhibitor. The molecule is found in some plant seeds and is used by Indigenous Amazonian cultures together with dimethyltryptamine (DMT) in the psychoactive brew ayahuasca. Harmine lengthens the psychoactive experience by inhibiting the enzyme monoamine oxidase A, which otherwise degrades neurotransmitters, including DMT. But this property makes harmine toxic at high levels, so Ermolaeva is looking at alternative compounds.

Neuroscientist Maiken Nedergaard of the University of Rochester Medical Center agrees that sleep facilitates DNA repair but says it has an even more important function: “There’s no doubt that we sleep for the brain.” Sleep is when we clean away the potentially toxic substances often associated with age-related neurodegenerative diseases. This includes the peptide amyloid-β, whose accumulation is associated with Alzheimer’s disease, and the protein α-synuclein, associated with Parkinson’s disease.

In 2012 Nedergaard discovered the glymphatic system, the brain’s waste-clearing network. Unlike most organs, which remove waste via the lymphatic system, the brain flushes out waste during sleep by flushing cerebrospinal fluid through open channels that run parallel to arteries and veins (Sci. Transl. Med. 2012, DOI: 10.1126/scitranslmed.3003748). The process is controlled by the neurotransmitter noradrenaline. “When we go to bed, it’s the fall of noradrenaline that opens up the valve” of the glymphatic system, Nedergaard explains. This opening can’t happen when the brain is awake as it would interfere with neurotransmitter activity.

The brain-clearing system starts to degrade with age, alongside sleep quality, and Nedergaard says that degradation might explain why poor sleep seems to hasten the progression of neurodegenerative disease (Science 2020, DOI: 10.1126/science.abb8739). But she thinks a way to mimic the process with an alternative therapy that does not also require sleep is unlikely to exist. “I don’t think you could ever clean your brain when you are awake,” she says.

The bumpy road to mimetic therapies

But while some aspects of a healthy lifestyle can’t be replaced with a pill, some researchers are still confident that at least some of the positive benefits of a healthy lifestyle can be mimicked.

Ermolaeva says that mimetic ability doesn’t mean we should give up the gym and start piling on the calories. “The best mimetic of a healthy lifestyle is a healthy lifestyle,” she says. But mimetics could be useful at times, she says, like for shift workers who otherwise experience disturbances to healthy routines. “I see it more as a therapy for groups of people that cannot afford a healthy lifestyle, but of course, it will also help those that have bad habits.”

Healthy-lifestyle mimetics could also be useful in treating particular diseases. Elgendy says his exercise mimetic is being investigated for neurodegenerative diseases, heart failure, and kidney disease. Handschin is focusing on treating age-related muscle wasting known as sarcopenia and cancer cachexia, the muscle loss occurring in some cancer patients, often leading to poorer cancer prognoses.

Going from promising results to a final product, however, is not guaranteed, and some potential mimetics have already failed to meet expectations in human trials. Back in 2009, Frank Madeo and Tobias Eisenberg from the University of Graz identified the naturally occurring polyamine spermidine as a caloric-restriction mimetic (Nat. Cell Biol. 2009, DOI: 10.1038/ncb1975).

But then a 12-month randomized clinical trial to test spermidine’s ability to slow cognitive decline in older adults showed no significant effect versus a placebo (JAMA Network Open 2022, DOI: 10.1001/jamanetworkopen.2022.13875). Spermadine is still being studied to assess its impact on metabolism, the immune system, and vasculature.

Handschin is also cautious about finding mimetics that can fully replicate a healthy lifestyle. With exercise, for example, so many organs and processes are involved. “I doubt that we’ll find this one compound that does everything,” he says. “But I think there’s good evidence that we might be able to find partial exercise mimetics or partial antiaging drugs that target certain pathways, and then [we can] elicit beneficial effects.”

Rachel Brazil is a freelance writer based in London.