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Exercise: A true fountain of youth

What if I told you there was a pill that could improve fitness, strength, mental well-being, cognitive function, and among all extend your lifespan? 

Hippocrates once said: “All parts of the body, if used in moderation and exercised in labors to which each is accustomed, become thereby healthy and well developed and age slowly; but if they are unused and left idle, they become liable to disease, defective in growth and age quickly.” However, though this era of modernization has brought us many groundbreaking medications that improve our health, many have forgotten the most simple and effective pillar of health, exercise.

Cardiorespiratory fitness

The first evidence for the benefit of physical activity came from an epidemiological study in 1953 that showed a lower risk of coronary heart disease (CHD) in physically active conductors versus inactive bus drivers (Morris and Crawford, 1958). Since then, a multitude of evidence have shown that exercise is unequivocally a health booster.

VO2max is a measure of the maximum amount of oxygen the body can utilize and is an incredible marker of cardiorespiratory fitness and mortality. There are many studies show the benefits of a higher VO2max, one of them with 1.1 million person-years (a lot) showed that compared to the people with top 5% of VO2max, the people with bottom 25% of VO2max had an over 5-fold difference in mortality rate (Mandsager et al., 2018). There are plenty of studies that show exercise of any form can increase VO2max and subsequently reduce mortality (Carazo-Vargas and Moncada-Jiménez, 2015). Generally, with lifelong aerobic exercise training, trained individuals have the same VO2max as a sedentary individual 4 decades younger (Booth, Roberts and Laye, 2012).

Figure 1: Comparison of all-cause mortality between groups with different VO2max. A hazard ratio (HR) of 5.04 means that compared with elite VO2max, those with low VO2max have a 5 times higher chance of dying of any cause. Image adapted from “Association of Cardiorespiratory Fitness With Long-term Mortality Among Adults Undergoing Exercise Treadmill Testing” (Mandsager et al., 2018).

Metabolic health

A randomized controlled trial back in 2002 showed that intensive lifestyle (diet and exercise) intervention reduced type-2 diabetes prevalence in high-risk adults by 58% compared to the no-interventions group, and was even more effective than metformin (a common drug used to treat type-2 diabetes) (Knowler et al., 2002). Even if we removed the diet intervention, exercise alone reduced the onset of type-2 diabetes by 46% in a cohort from China (Pan et al., 1997). Although exercise mainly mediates this effect through weight loss, even in the absence of weight loss, exercise can independently reduce diabetes incidence (Hamman et al., 2006).

Figure 2: Cumulative incidence of diabetes in the 2002 Diabetes Prevention Program clinical trial. Image taken from “Reduction in the Incidence of Type 2 Diabetes with Lifestyle Intervention or Metformin” (Knowler et al., 2002).

Insulin normally induces GLUT4 translocation to the plasma membrane to allow glucose entry into the cell (Vargas, Podder and Carrillo Sepulveda, 2022). Type-2 diabetic patients have cells that are resistant to insulin’s effect, which increases their blood glucose level (Saini, 2010). Exercise can increase the uptake of blood glucose independently of insulin action by activating a downstream pathway of insulin that facilitates GLUT4 translocation to the plasma membrane (Deshmukh et al., 2006). Exercise can also improve the sensitivity of body cells to insulin (Stanford and Goodyear, 2014). Furthermore, resistance exercise can increase muscle mass which could contribute to blood glucose uptake, without necessarily modifying insulin sensitivity (Pesta et al., 2017).

Figure 3: Proposed mechanism of exercise’s effect on type 2 diabetes. Image taken from “Exercise and type 2 diabetes: molecular mechanisms regulating glucose uptake in skeletal muscle” (Stanford and Goodyear, 2014).

In terms of blood pressure, exercise has been consistently shown in randomized controlled trials to reduce systolic blood pressure by about 4-5 mmHg (Edwards et al., 2023). Other risk factors for disease such as BMI, triglyceride levels, LDL-cholesterol levels, and HDL-cholesterol levels also seem to be benefitted by exercise (Busnatu et al., 2022).

Figure 4: Physiological benefits of exercise. Image taken from Swiss Health Web.

Aside from the weight-loss-induced benefits, exercise could improve these risk factors through regulation of endothelial function (Gambardella et al., 2020), increased lipoprotein-lipase activity, decreased PCSK9 levels, and increased reverse cholesterol transport, though these mechanisms are not yet fully understood (Wang and Xu, 2017).

Muscular strength

Sarcopenia is a growing public health concern, especially in older adults, characterized by muscle atrophy and loss of strength. This is very harmful in late life as it could prevent people from living a proper life without external assistance. Muscle strength starts to decrease after 50–60 years of age at the rate of decline of approximately 2%–4% per year (Delmonico et al., 2009).

The pathogenesis of sarcopenia remains to be fully elucidated but is proposed to involve mitochondrial dysfunction, excessive myostatin (a protein that inhibits muscle growth), and inflammatory cytokines (Yoo et al., 2018). An active lifestyle has been reported to attenuate sarcopenia and prevent body fat accumulation and inflammation. Resistance exercise promotes muscle hypertrophy and improves virtually all of the physiological mechanisms in the nervous system and the muscular system known to influence strength (Law, Clark and Clark, 2016). Exercise, especially endurance-based on the other hand also stimulates mitochondrial biogenesis and improves mitochondrial function (Baar et al., 2002). Indeed, a Cochrane review in 2009 including over 6,700 participants concluded that progressive resistance training improved physical activity, reduced functional limitations, improved strength, and reduced osteoarthritis-associated pain (Liu and Latham, 2009).

Figure 5: Mechanisms whereby exercise can act on to reduce sarcopenia. Image taken from “Role of exercise in age-related sarcopenia” (Yoo et al., 2018).

Cognitive function

The ability of our brain to perform its function and support our daily lives is increasingly becoming important, especially to fend off diseases such as Alzheimer’s disease.

Physical exercise has been shown to increase gray matter volume (the region of information processing) in the frontal and hippocampal region of the brain (Colcombe et al., 2006). In children, exercise is related to increased white matter integrity in sections of the corpus callosum, corona radiata, and superior longitudinal fasciculus (Chaddock-Heyman et al., 2014).

In terms of outcome data, epidemiological studies showed that physical exercise enhances cognitive functions in young and older adults, improves memory abilities, efficiency of attentional processes and executive-control processes (Mandolesi et al., 2018). Furthermore, structural changes following physical exercise have been linked to better academic achievement in comparison to sedentary individuals (Lees and Hopkins, 2013). Similarly, it has been also showed that children who practice regular aerobic activity performed better on verbal, perceptual and arithmetic test in comparison to sedentary children (Sibley and Etnier, 2003). Many studies have also proposed physical exercise in reducing age-related cognitive decline, the risk of developing dementia, the level of deterioration in executive functions and improving the quality of life (Mandolesi et al., 2018).

At the molecular level, motor activity causes changes in neurotransmitters such as serotonin, noradrenaline, and acetylcholine (Lin and Kuo, 2013) and induces the release of the brain-derived neurotrophic factor (BDNF) (Lafenetre et al., 2011) and the insulin-like growth factor-1 (IGF-1) (van Praag, 2009).

Figure 6: Conceptual model of mechanisms of physical activity (PA) at multiple levels of analysis. Image taken from “Mediators of Physical Activity on Neurocognitive Function: A Review at Multiple Levels of Analysis” (Stillman et al., 2016).

Mental health

Our health doesn’t only matter from a physical perspective but also mentally. Many studies support physical activity as a noninvasive therapy for mental health. In children, physical exercise is correlated with high levels of self-efficacy, tasks goal orientation, and perceived competence (Biddle et al., 2011). In youth and adults, most studies show that physical exercise is associated with better mood and self-concept (Penedo and Dahn, 2005), whereas in elderly populations, physical exercise helps maintain independence by favoring social relations (Stessman, 2009). Epidemiological studies have also consistently shown that physical exercise reduces depression (Mammen and Faulkner, 2013) and anxiety (DeBoer et al., 2012). Controlled intervention studies have also shown that physical exercise reduces depressive and anxious symptoms (Gordon et al., 2017, Gordon et al., 2018).

These beneficial effects could be explained by increased cerebral blood flow and in maximal oxygen consumption, delivery of oxygen to cerebral tissue, and increased serum concentrations of endocannabinoid receptors (Mandolesi et al., 2018). Physical exercise increases the level of serotonin and beta-endorphins (Young, 2007).

Figure 7: Benefits of exercise on mental health. Image taken from Priory.

Practical recommendations

If this all sounds too scientific to you, just know that exercise is like a wonder pill. Even then, we don’t even need to train like elite athletes to reap these benefits. Most evidence shows that a lot of the benefits of exercise can be acquired through just 150 minutes per week of moderate-intensity aerobic activity, or 75 minutes per week of vigorous aerobic activity, or a combination of both, preferably spread throughout the week. Resistance exercises should also be performed at least 2 days a week (American Heart Association, 2018). That being said, let’s not complicate things. The best exercise regimen is one that you can stick to, and we should all appreciate this pill that can add years to our life and life to our years.


Article prepared by: Jared Ong Kang Jie, R&D Director of MBIOS 2023/2024

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