Chasing the fountain of youth

mouse models for aging research

If you needed another reason to add “exercise more” to your New Year’s resolutions, look no further- exercise will keep you looking, feeling, and thinking young.  Aging is the major risk factor for several diseases including cancer, diabetes, cardiovascular and neurodegenerative disease, and research has shown that exercise and physical activity delay the onset of age-related muscle loss, motor instability, and cognitive decline.  The molecular mechanisms that underlie exercise’s mitigating effects on disease are not well understood, but recent studies in humans and mice are shedding light on the mediators of these phenomena to provide guidance for more focused treatment options and healthier lifestyle choices for our aging population.


Exercise reduces the culprit of age-related disease: inflammation

The role of chronic, low-level inflammation in disease is becoming increasingly appreciated, and several studies have demonstrated that inflammatory mediators increase as animals age (for a review, see Pawelec et al.).  Inflammation can negatively affect many biological processes, including metabolism, brain physiology, cardiovascular function, and genome stability, and can increase susceptibility to many diseases.  In C57BL/6 NFkB-deficient mice (B6.Cg-Nfkb1tm1Bal/J (006097)), a mouse model of chronic inflammation, pro-inflammatory IL-6 levels rise as animals age.  Increased T cell infiltration into the liver and spleen also are observed.  Further, these observations correlate with premature aging and impaired tissue regeneration in these mice which result from telomere dysfunction and enforced senescence. Likewise, age-related inflammation is observed in B6D2F1 wild-type mice, but aerobic exercise reduces the age-associated increases in proinflammatory cytokines, demonstrating that exercise negatively regulates inflammation.  Finally, in a study conducted in centenarian humans, inflammation biomarker scores were a better predictor for longevity than chronologic age, gender, or telomere length.  Coupling comprehensive studies in humans with deeper mechanistic studies in mice should help to uncover a clearer picture of the relationship between aging, exercise, and inflammation.


Mitochondria: the mediator between exercise, inflammation, and aging

Mitochondrial abnormalities are other phenomena that are associated with the age-related disease and age-dependent energy deficits.  Mitochondria are the engines that drive cellular processes by freeing up energy, in the form of ATP, through a process called oxidative phosphorylation.  Defective oxidative phosphorylation resulting from the mitochondrial dysfunction occurs with aging and various other clinical disorders, and typically coincides with excess Reactive Oxygen Species (ROS) synthesis.  Elevated ROS increases oxidative stress in cells, thereby contributing to mitochondrial DNA (mtDNA) mutations, inflammation, cell death, and tissue damage.  Because long-term exercise can induce mitochondrial biosynthesis and increase function, mitochondria may be the hidden link between exercise, inflammation, and aging.

In a study using a mouse model of mitochondrial dysfunction that phenocopies human aging (B6.129S7(Cg)-Polgtm1Prol/J (017341), a sedentary lifestyle correlated with increased mortality and other age-related conditions, including weight loss, reduced mobility, alopecia, and poor body condition. The observed effects were inhibited by 5 months of forced endurance exercise. The enforced exercise regimen also restored mitochondrial oxidative capacity, increased mitochondrial biosynthesis, and prevented accumulations of mutations in mtDNA. These data provide evidence that disruptions in mitochondrial oxidative functions contribute to age-related deterioration and that exercise has the ability to reverse them.


Exercise enhances memory, learning and neurogenesis

Inflammation is also bad for the brain, primarily by impairing neurogenesis.  This is most easily observed in the hippocampus.  The hippocampus is a brain region involved in memory and navigation, and is one of the regions first affected in Alzheimer’s disease.  In one study, female C57BL/6J mice, aerobic exercise induced neurogenesis in the dentate gyrus of the hippocampus and enhanced learning ability. In another study, exercise in aged C57BL/6 mice mitigated age-dependent changes in mitochondrial biogenesis and energy metabolism in the entire brain. These studies demonstrate that exercise can counteract some of the age-dependent changes that occur in the brain to promote neuron development and function.


Exercise reduces susceptibility to certain cancers

Most cancer cases are diagnosed later in life, and cancer diagnoses often are associated with chronic, low-grade inflammation.  Studies have shown that exercise reduces the prevalence of some cancers - colon, skin, and breast cancers, for example - but not others.  Studies in mice have been used to study the effects of exercise on different cancer susceptibilities and treatment outcomes. In one study using C57BL/6J-ApcMin/J (002020) mice, voluntary exercise reduced both overall tumor number and tumor size.  In another study using FVB-Tg(MMTV-Erbb2)NK1Mul/J (005038) mice, running not only reduced mammary tumor growth and tumor volume in a frequency-dependent manner, but exercised mice that developed tumors had reduced overall inflammation as compared to non-exercised and tumor-bearing controls. Together, these results demonstrate the direct relationship between exercise, inflammation and oncogenesis.

Additional investigations dissecting the intersections between inflammation, exercise, aging, and disease development in both humans and mice undoubtedly will continue.  Although conclusions drawn from some studies may conflict (see, for example, Mehl et al. and Colbert et al.), one thing is for sure:  low- to moderate-intensity exercise performed on a regular basis has the potential to delay the onset of disease and add years to your life.  Just make sure to start slow, and clear it with your doctor first!