Exerkines Offer New Vistas in Fighting Age-Related Decline

Exercise is more than just a routine of sweating and counting repetitions; it is increasingly recognized as a powerful biological tool that taps into the body’s own chemical arsenal to slow the progression of age-related decline. Fueled by the discovery of so-called “exerkines”—the bioactive substances produced and secreted by muscle, liver, adipose tissue, bone, and even the brain in response to physical activity—scientists are redefining how we look at exercise’s impact on aging. For decades, exercise was lauded mainly for improving cardiovascular health and helping to manage weight. Yet a surge of research into exerkines now reveals that physical activity also triggers an intricate cascade of molecular signals. These signals can help the body fend off inflammation, keep energy balance in check, repair tissues, and even protect the brain against the cognitive decline so often associated with later life. Far from being mere passive recipients of mechanical stress, our cells and tissues respond dynamically to repeated bouts of movement, releasing specialized molecules that reinforce health on multiple fronts.

Imagine that you are in your sixties or seventies, and on a brisk walk. Your muscles contract, setting off small waves of calcium and other signaling molecules. In response, your skeletal muscle cells secrete a host of myokines into your bloodstream—molecules such as interleukin-6 (IL-6) and irisin. Meanwhile, your adipose tissue, sensing metabolic demands, releases adipokines that fine-tune insulin sensitivity. Your liver, stirred by changes in blood flow and metabolic substrates, sends out hepatokines such as fibroblast growth factor 21 (FGF21). And your bones, subjected to the forces of gravity and muscle tension, secrete osteocalcin or other osteokines that preserve skeletal integrity. Even your brain—through glial cells or neurons—contributes neurokines that bolster synaptic plasticity. All these exerkines then travel through the bloodstream, coordinating with different organs, collectively pushing back against the harmful effects of age-related stress and inflammation.

It is well known that aging coincides with a series of systemic changes—reduced muscle mass (sarcopenia), diminishing bone density (osteoporosis), elevated inflammation (“inflammaging”), and a decline in mitochondrial quality. The danger is that these changes feed into each other, leading to a spiraling loss of vitality. But the exerkines triggered by regular physical activity can break this vicious cycle. For instance, certain exerkines promote a shift away from chronic inflammation by boosting the production of anti-inflammatory mediators like interleukin-10 (IL-10) and restricting pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α). Others enhance the oxidative capacity of skeletal muscle, reducing the accumulation of reactive oxygen species (ROS) and preventing mitochondrial decay—major contributors to cellular dysfunction in older adults.

Scientists have begun to pinpoint precisely how exerkines exert these protective effects. One factor is the well-known molecule IL-6, which can exhibit pro-inflammatory behavior in certain contexts but acts as an anti-inflammatory signal during and immediately after exercise. Another is irisin, a hormone-like factor that helps convert white adipose tissue into a more metabolically active “beige” fat, raising one’s resting energy expenditure while improving insulin sensitivity and metabolic health. Meanwhile, fibroblast growth factor 21 (FGF21), secreted mainly by the liver, exerts beneficial effects on glucose control and lipid metabolism, thus lowering one’s vulnerability to type 2 diabetes. Myostatin, once considered only a negative regulator of muscle growth, has emerged as a possible modulator of tumor suppression. Apelin, another exerkine, fosters the health of both bone and muscle tissue, helping older bodies withstand the rigors of daily life. And in the brain, molecules like clusterin or glycosylphosphatidylinositol-specific phospholipase D1 (GPLD1) can dampen inflammation and shore up neural plasticity, safeguarding cognition in older adults.

At first, it may sound like an astonishing synergy: how can the same physical movement help the heart, bones, muscles, immune system, and even the brain? But the body’s architecture is deeply interconnected, and exerkines serve as the biochemical messengers that tie all these benefits together. Perhaps the clearest example is skeletal muscle, the largest organ by mass in most people, which rapidly communicates with other tissues during a workout. The molecular signals it emits—the myokines—can travel to the liver to promote better fat oxidation, or to the brain to encourage synaptic plasticity. They may also act on the immune cells, fine-tuning the balance between pro-inflammatory and anti-inflammatory signaling. Likewise, adipose tissue secretes adiponectin, which fosters fatty acid oxidation and reduces insulin resistance in muscle and liver, while also modulating inflammatory processes system-wide. This level of cross-organ “conversation” explains why a simple brisk walk or a few sets of resistance exercises per week can lower the risk of so many age-related conditions—from cardiovascular disease and type 2 diabetes to osteoporosis and some cancers.

Given the multiplicity of exerkines, it should be no surprise that different forms of exercise generate distinct benefits. The recommendation for older adults, proposed by various international guidelines, generally includes a combination of resistance training, aerobic exercise, and balance activities. Resistance or weight training stimulates muscle hypertrophy and strength gains, spurring the release of exerkines that specifically promote muscle repair and anabolism. Aerobic exercises like walking, jogging, or cycling, at intensities around 55–70% of maximum heart rate, are associated with improved cardiovascular function, higher levels of beneficial cytokines such as IL-10, and better glycemic control. Balance and flexibility exercises, such as yoga and tai chi, are no less important; they may not generate as high an acute exerkine surge as intense resistance training or cardio, but they do help preserve neuromuscular coordination and reduce the risk of falls—a critical factor in healthy aging.

One of the cornerstones of exerkine research is the notion that improving mitochondrial function is a central mechanism of “exercise as medicine.” With age, mitochondria in cells become less efficient at producing ATP (adenosine triphosphate), and they accumulate oxidative damage. Exercise can mitigate this by increasing the expression of key enzymes like glutathione peroxidase (GPx), superoxide dismutase (SOD), and heme oxygenase-1 (HO-1), which help neutralize free radicals. ROS no longer run rampant, so the negative feedback loop leading to further mitochondrial damage is dampened. Meanwhile, exerkines promote the production of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a major driver of mitochondrial biogenesis. As a result, older individuals who engage in physical activity can regenerate healthier mitochondria, thus powering their cells more effectively. The payoff is less cellular senescence, improved nutrient sensing, and often a reduction in chronic inflammation.

It is important to note that the synergy between exercise and exerkines extends into domains like cognitive function. Regular training fosters a rise in brain-derived neurotrophic factor (BDNF), a neurotrophin essential for neuronal survival, synaptic plasticity, and hippocampal neurogenesis. This helps guard against the cognitive deficits associated with disorders such as Alzheimer’s disease. Some exerkines, such as glycosylphosphatidylinositol-specific phospholipase D1 (GPLD1) and platelet factor 4 (CXCL4), have also been implicated in hippocampal neurogenesis, encouraging the generation of new neurons and reversing certain aspects of age-related mental decline. These discoveries resonate strongly with observational data showing that physically active older adults frequently show slower cognitive decline and lower incidence of neurodegenerative conditions.

For those concerned about type 2 diabetes, exercise again steps in with an exerkine-mediated strategy. Muscle contraction not only draws glucose into cells via transporters like GLUT4, it also triggers the release of certain hepatokines from the liver and adipokines from fat that normalize blood sugar levels. FGF21, for instance, fosters insulin sensitivity, while HSP72 (heat shock protein 72) can prevent misfolded protein accumulation in pancreatic beta cells. Even short bursts of activity can drive these beneficial changes. Though many older people worry about whether they can safely engage in vigorous workouts, the research points to moderate, consistent habits—like walking daily or lifting light weights multiple times a week—as enough to catalyze these systemic benefits.

Another striking area of discovery is the way exerkines appear to influence bone health. Osteocalcin, produced by bone in response to the mechanical load from weight-bearing exercise, helps maintain bone mineral density and appears to have metabolic functions that extend beyond bone. It may, for example, improve insulin sensitivity. Meanwhile, molecules such as TGF-β1 and apelin, also upregulated by exercise, can help coordinate bone formation and muscle mass. For older adults whose bones grow increasingly fragile, these factors are a ticket to reduced fracture risk and better musculoskeletal resilience. In some scenarios, the synergy between osteokines and myokines can help accelerate bone healing after injury or surgery, a tremendous boon for those in advanced age.

Add to this the remarkable possibility that exerkines carry at least some anti-cancer properties, and exercise’s significance in health management gains still more luster. Myostatin, ironically known for suppressing muscle growth, has recently been linked to anti-tumor functions in certain tissues, possibly by dampening pathways that drive unchecked proliferation. Irisin, once studied for its effect on adipose tissue browning, also shows promise as an anti-tumor agent in preclinical models, often by boosting the immune system’s detection of malignant cells or by altering local inflammatory signals that help tumors thrive. Even though these studies are preliminary, they open an exciting dimension of research: perhaps a consistent exercise routine could lower both the risk of developing cancer and, in some cases, slow progression for those who already have it.

Despite the avalanche of positive evidence, we must tread carefully. Not all forms or intensities of exercise deliver uniform exerkine responses. Overtraining—exercising too vigorously or too frequently—can create oxidative stress or immune suppression, especially in older individuals who may have other comorbidities. The goal, therefore, is moderation and personalization: designing a plan that taps into the beneficial exerkine output without overwhelming the body’s capacity to recover. Many new areas of research revolve around “exercise mimetics,” compounds that mimic the effect of exerkines by targeting the same molecular pathways. For individuals too frail to exercise adequately, such compounds could theoretically provide the health benefits of a workout. But the nuance is that exercise is not merely a pill to be replaced; it sets in motion large-scale mechanical, neural, and metabolic processes that may not be fully replicated by a single compound or cocktail.

What will the future hold for this intriguing domain of exerkines and anti-aging strategies? One possibility is that health practitioners will monitor exerkine levels in the bloodstream to gauge whether an older adult’s exercise regimen is truly effective. Another is that gene- or cell-based therapies could selectively increase expression of beneficial exerkines, or block “rogue” molecules that hamper healthy aging. As more is uncovered about how these molecules act and interact, a new generation of geriatric medicine could arise, leveraging exerkines to combat conditions as diverse as Alzheimer’s, frailty, and diabetes. Pharmacologists already see exerkines as potential “druggable” targets. For instance, if we can harness the browning effect of irisin safely, we might treat obesity without radical changes in diet. If we can modulate clusterin or BDNF effectively, we might slow cognitive decline. Conversely, controlling overactive inflammatory exerkines in certain autoimmune settings might stave off age-associated autoimmune conditions.

Yet, in the midst of all these futuristic innovations, the core message remains clear: regular movement, even in modest doses, is already our best bet for “turning on” these beneficial exerkines. Where certain pharmaceutical avenues may take years to become safe and widely available, everyday exercise is accessible now, with little risk and abundant upside. Medical experts emphasize that older adults should combine strategies: build in some resistance training to preserve muscle mass and bone density, incorporate aerobic exercise to bolster cardiovascular and metabolic function, and do balance activities to reduce fall risk and maintain neural reflexes. These are not complicated tasks, but the molecular payoffs—in the form of exerkine release—can be profound.

Ultimately, the story of exercise-induced exerkines is one of the most compelling examples of how our bodies are designed for movement, and how that movement orchestrates a symphony of positive biological signals. By activating these signals through conscious, consistent activity, we tap into a powerful, evolution-built mechanism that defends us against the degradations of time. Gone are the days when we could think of exercise merely as a means to burn calories. Instead, each session of walking, resistance training, or mindful balance exercises sets off thousands of molecular changes that can be harnessed to keep us healthier for longer. It is a powerful illustration that our biology wants us to move, and in moving, we coax our cells to produce molecules that can keep the ravages of age at bay.

As researchers continue to refine our understanding, we may see more targeted advice on the most effective exercise “doses,” frequencies, and intensities for stimulating beneficial exerkines. We may also see novel interventions that help older adults overcome barriers to physical activity, from wearable technology that tracks functional movement patterns to community programs aimed at delivering personalized exercise regimens. If further breakthroughs arrive with safe and effective exercise mimetics, so much the better. Yet for now, the basic science underscores a unifying conclusion: exercise remains one of our most potent forms of preventive medicine, not just for the muscle and cardiovascular advantages, but for the invisible molecular crosstalk that might very well determine how gracefully and how long we age.

Subject of Research: Exercise and Exerkines in Anti-Aging and Disease Prevention
Article Title : Exercise and Exerkines: Mechanisms and Roles in Anti-Aging and Disease Prevention
News Publication Date : February 2025
Article Doi References : https://doi.org/10.1016/j.exger.2025.112685
Keywords : Exerkines, Anti-aging, Exercise Physiology, Mitochondrial Function, Muscle Mass, Inflammaging, Cognitive Decline, Metabolic Homeostasis, Bone Density

Tags: Anti-agingBone Density MaintenanceCognitive Decline PreventionExercise PhysiologyExerkinesGeroscienceInflammagingMetabolic HomeostasisMitochondrial FunctionMolecular SignalingMuscle Mass PreservationNeuroprotection