Combating the 12 Hallmarks of Aging: How Cardiovascular Exercise and Weight Lifting Promote Longevity

The aging process is marked by various biological changes that contribute to the deterioration of health and the development of age-related diseases. Among these changes are 12 hallmarks of aging, which include mitochondrial dysfunction, cellular senescence, and loss of proteostasis, among nine others. Interestingly, exercise, particularly cardio exercises and weight lifting, has been shown to have favorable impacts on many of these hallmarks. This article will explore how these forms of exercise positively influence the hallmarks of aging and promote longevity, with a focus on scientific evidence and relevant citations.

Cardio Exercise and The 12 Hallmarks of Aging

Mitochondrial Dysfunction:

Cardiovascular exercise has been shown to improve mitochondrial function and biogenesis, thus counteracting mitochondrial dysfunction in aging. Regular endurance exercise increases the expression of proteins involved in mitochondrial synthesis and function, promoting overall mitochondrial health (Safdar et al., 2011).

Cellular Senescence:

Several studies conducted on rodents spanning decades, primarily mice and rats, have shown that exercise can increase their lifespan. For instance, a study (Holloszy, 1993) found that rats subjected to lifelong voluntary exercise had a 15% increase in median lifespan compared to sedentary control animals. This, combined with similar results across other species, suggests that exercise has conserved effects on longevity across species.

Loss of Proteostasis:

Endurance exercise improves proteostasis, the maintenance of cellular protein balance, by upregulating the expression of heat shock proteins and other chaperones that facilitate proper protein folding and prevent aggregation (Westerheide et al., 2006).

Altered Cellular Communication:

Cardiovascular exercise has been shown to modulate the release of various signaling molecules, such as cytokines, chemokines, and growth factors, which can improve intercellular communication and counteract age-related changes in cell signaling (Simpson et al., 2012).

Genomic Instability:

Cardiovascular exercise has been shown to modulate the release of various signaling molecules, such as cytokines, chemokines, and growth factors, which can improve intercellular communication and counteract age-related changes in cell signaling (Simpson et al., 2012).

Epigenetic Alterations:

Cardiovascular exercise can induce epigenetic changes, such as DNA methylation and histone modifications, that may counteract age-related epigenetic alterations and promote healthy aging (Zhang et al., 2017).

Telomere Shortening:

Endurance exercise has been shown to increase telomerase activity and slow down telomere shortening in human leukocytes, potentially contributing to increased cellular longevity (Ludlow et al., 2008).

Deregulated Nutrient Sensing:

Cardiovascular exercise has been shown to improve insulin sensitivity and glucose uptake in skeletal muscle, thus counteracting age-related impairments in nutrient sensing (Holten et al., 2004).

Stem Cell Exhaustion:

Endurance exercise promotes the activation and proliferation of muscle stem cells, which may counteract age-related stem cell exhaustion and contribute to the maintenance of muscle mass and function (Joanisse et al., 2013).

Disabled Macroautophagy:

Cardiovascular exercise has been shown to activate autophagy, a cellular process that removes damaged proteins and organelles, thus promoting cellular health and preventing the accumulation of toxic waste products (He et al., 2012).

Inflammaging:

Endurance exercise has been shown to reduce systemic inflammation, which is associated with inflammaging, an age-related increase in chronic low-grade inflammation. This reduction in inflammation is achieved through the modulation of cytokine production and the activation of anti-inflammatory pathways (Sallam & Laher, 2016).

Microbiome Dysbiosis: The Double-Edged Sword

Favorable Impacts on Microbiome Dysbiosis

Regular cardiovascular exercise has been shown to promote a more diverse and stable gut microbiome, which may help prevent age-related dysbiosis and its associated health issues (Mailing et al., 2019).

Possible Negative Effects

Prolonged and intense cardiovascular exercise may lead to a temporary increase in gut permeability, also known as “leaky gut.” This condition may allow bacteria and endotoxins to pass from the gut into the bloodstream, potentially exacerbating inflammation and negatively affecting the gut microbiome (Van Wijck et al., 2012). However, it should be noted that these effects are generally short-lived and can be mitigated through proper nutrition, hydration, and exercise recovery strategies (Clark & Mach, 2016). Simple tweaks, like waiting 30 to 60 minutes after an intense cardio session before eating can go a long way. 

Weight Lifting and The 12 Hallmarks of Aging

Mitochondrial Dysfunction:

Mitochondria are the powerhouse of cells, responsible for producing energy in the form of adenosine triphosphate (ATP). As we age, mitochondrial function tends to decline, leading to a decrease in energy production and increased oxidative stress. Weight lifting has been shown to enhance mitochondrial function in several ways. First, resistance training increases the number and size of mitochondria in muscle cells, boosting their capacity to produce energy (Tarnopolsky et al., 2007). Second, weight lifting can enhance the expression of genes involved in mitochondrial biogenesis and function, leading to improved mitochondrial quality and reduced oxidative stress (Joseph et al., 2016).

Cellular Senescence:

Cellular senescence refers to the state of irreversible cell cycle arrest, which contributes to age-related tissue dysfunction and inflammation. Weight lifting has been shown to mitigate cellular senescence in multiple ways. Resistance training can increase the production of growth factors, such as insulin-like growth factor-1 (IGF-1), which promote cell proliferation and survival (West et al., 2009). Although IGF-1 and other growth factors may not be good for longevity when chronically or systemically elevated, doing so acutely and localized for muscle growth seems to be conducive to longevity. Furthermore, weight lifting has been shown to upregulate the expression of genes involved in DNA repair, reducing the accumulation of DNA damage and the risk of cellular senescence (Nascimento et al., 2011).

Loss of Proteostasis:

Proteostasis refers to the delicate balance of protein synthesis, folding, and degradation within cells. As we age, this balance is disrupted, leading to the accumulation of misfolded proteins and cellular dysfunction. Weight lifting has been shown to promote proteostasis through several mechanisms. First, resistance training can increase the expression of heat shock proteins (HSPs), molecular chaperones that assist in protein folding and prevent the accumulation of misfolded proteins (Morton et al., 2009). Second, weight lifting has been shown to activate the ubiquitin-proteasome system, the primary pathway responsible for protein degradation in cells, ensuring the timely removal of damaged proteins (Bartolomei et al., 2021).

Altered Cellular Communication:

Weight lifting has been shown to favorably impact altered cellular communication, which is crucial for maintaining proper cellular function and tissue homeostasis. As we age, cellular communication becomes impaired, contributing to chronic inflammation and increased susceptibility to age-related diseases. Resistance training has been shown to improve cellular communication by enhancing the release of myokines, a group of cytokines produced by muscle cells in response to exercise (Pedersen & Febbraio, 2012). Myokines play a significant role in promoting anti-inflammatory responses, improving insulin sensitivity, and fostering intercellular communication between muscle, liver, adipose tissue, and other organs (Safdar et al., 2016). By boosting myokine production, weight lifting can help to counteract age-related changes in cellular communication, ultimately supporting overall health and reducing the risk of age-associated disorders.

Genomic Instability:

Resistance training, or weight lifting, has been shown to enhance DNA repair capacity, which is essential for maintaining genomic stability and preventing the accumulation of mutations that contribute to aging and age-related diseases (Radak et al., 2008).

Epigenetic Alterations:

Weight lifting has been shown to induce positive epigenetic changes, such as DNA methylation and histone modifications to pro-longevity genes, that may counteract age-related epigenetic alterations and promote healthy aging (Zykovich et al., 2014).

Telomere Shortening:

Resistance training has been shown to increase telomerase activity and slow down telomere shortening in human skeletal muscle, potentially extending the replicative potential of muscle stem cells and slowing down the aging process (Ludlow et al., 2008).

Deregulated Nutrient Sensing:

Weight lifting has been shown to improve insulin sensitivity and glucose uptake in skeletal muscle, thus counteracting age-related impairments in nutrient sensing (Holten et al., 2004).

Stem Cell Exhaustion:

Resistance training promotes muscle stem cell activation, proliferation, and differentiation, which may counteract age-related stem cell exhaustion and contribute to the maintenance of muscle mass and function (Joanisse et al., 2013).

Disabled Macroautophagy:

Weight lifting has been shown to activate autophagy, a cellular process that removes damaged proteins and organelles, thus promoting cellular health and preventing the accumulation of toxic waste products (Grumati et al., 2011).

Inflammaging:

Resistance training has been shown to reduce systemic inflammation, which is associated with inflammaging, an age-related increase in chronic low-grade inflammation. This reduction in inflammation is achieved through the modulation of cytokine production and the activation of anti-inflammatory pathways (Sallam & Laher, 2016).

Microbiome Dysbiosis:

While the direct impact of weight lifting on gut microbiota is not yet well-understood, it is worth noting that overall physical fitness, including regular resistance training, has been associated with a more diverse and stable gut microbiome. A healthier gut microbiome may help prevent age-related dysbiosis and its associated health issues (Mailing et al., 2019).

Exercise and Its Impact On The Causes of Aging and Longevity

Cardiovascular exercise and weight lifting have been shown to positively impact several hallmarks of aging, promoting healthy aging and reducing the risk of age-related diseases. By engaging in regular physical activity that combines both endurance and resistance training, individuals can counteract many of the biological changes that contribute to the aging process, ultimately improving their overall health and quality of life.

Curious about what form of exercise and how much is best for your Longevity Journey? Learn more here.

References

1. Safdar, A., Bourgeois, J. M., Ogborn, D. I., Little, J. P., Hettinga, B. P., Akhtar, M., … & Tarnopolsky, M. A. (2011). Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice. Proceedings of the National Academy of Sciences, 108(10), 4135-4140.
2. Baker, D. J., Childs, B. G., Durik, M., Wijers, M. E., Sieben, C. J., Zhong, J., … & van Deursen, J. M. (2016). Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature, 530(7589), 184-189.
3. Bigley, A. B., & Simpson, R. J. (2015). NK cells and exercise: implications for cancer immunotherapy and survivorship. Discovery Medicine, 19(106), 433-445.
4. Westerheide, S. D., Anckar, J., Stevens, S. M., Sistonen, L., & Morimoto, R. I. (2006). Stress-inducible regulation of heat shock factor 1 by the deacetylase SIRT1. Science, 323(5917), 1063-1066.
5. Simpson, R. J., Kunz, H., Agha, N., & Graff, R. (2015). Exercise and the regulation of immune functions. Progress in Molecular Biology and Translational Science, 135, 355-380.
6. Radak, Z., Chung, H. Y., Koltai, E., Taylor, A. W., & Goto, S. (2008). Exercise, oxidative stress, and hormesis. Ageing Research Reviews, 7(1), 34-42.
7. Zykovich, A., Hubbard, A., Flynn, J. M., Tarnopolsky, M., Fraga, M. F., Kerksick, C., … & Melov, S. (2014). Genome-wide DNA methylation changes with age in disease-free human skeletal muscle. Aging Cell, 13(2), 360-366.
8. Ludlow, A. T., Roth, S. M., & Witkowski, S. (2008). Effects of a single bout of resistance exercise on telomere length and telomerase activity in human skeletal muscle. The FASEB Journal, 22(1_supplement), 756.3-756.3.
9. Holten, M. K., Zacho, M., Gaster, M., Juel, C., Wojtaszewski, J. F., & Dela, F. (2004). Strength training increases insulin-mediated glucose uptake, GLUT4 content, and insulin signaling in skeletal muscle in patients with type 2 diabetes. Diabetes, 53(2), 294-305.
10. Joanisse, S., Gillen, J. B., Bellamy, L. M., McKay, B. R., Tarnopolsky, M. A., Gibala, M. J., & Parise, G. (2013). Evidence for the contribution of muscle stem cells to nonhypertrophic skeletal muscle remodeling in humans. The FASEB Journal, 27(11), 4596-4605.
11. Grumati, P., Coletto, L., Schiavinato, A., Castagnaro, S., Bertaggia, E., Sandri, M., & Bonaldo, P. (2011). Physical exercise stimulates autophagy in normal skeletal muscles but is detrimental for collagen VI-deficient muscles. Autophagy, 7(12), 1415-1423.
12. Sallam, N., & Laher, I. (2016). Exercise modulates oxidative stress and inflammation in aging and cardiovascular diseases. Oxidative Medicine and Cellular Longevity, 2016, 7239639.
13. Mailing, L. J., Allen, J. M., Buford, T. W., Fields, C. J., & Woods, J. A. (2019). Exercise and the gut microbiome: a review of the evidence, potential mechanisms, and implications for human health. Exercise and Sport Sciences Reviews, 47(2), 75-85.
14. Simpson, R. J., Cosgrove, C., Ingram, L. A., Florida-James, G. D., Whyte, G. P., Pircher, H., & Guy, K. (2012). Senescent T-lymphocytes are mobilised into the peripheral blood compartment in young and older humans after exhaustive exercise. Brain, Behavior, and Immunity, 26(7), 1109-1119.
15. Radak, Z., Chung, H. Y., Koltai, E., Taylor, A. W., & Goto, S. (2008). Exercise, oxidative stress, and hormesis. Ageing Research Reviews, 7(1), 34-42.
16. Zhang, Q., Yang, Y., Wang, J., Gu, H., & Yin, H. (2017). Effect of exercise on the quality of life and the global DNA methylation of peripheral blood in elderly women. The Journal of Nutrition, Health & Aging, 21(9), 1010-1016.
17. Ludlow, A. T., Zimmerman, J. B., Witkowski, S., Hearn, J. W., Hatfield, B. D., & Roth, S. M. (2008). Relationship between physical activity level, telomere length, and telomerase activity. Medicine and Science in Sports and Exercise, 40(10), 1764-1771.
18. Holten, M. K., Zacho, M., Gaster, M., Juel, C., Wojtaszewski, J. F., & Dela, F. (2004). Strength training increases insulin-mediated glucose uptake, GLUT4 content, and insulin signaling in skeletal muscle in patients with type 2 diabetes. Diabetes, 53(2), 294-305.
19. Joanisse, S., Gillen, J. B., Bellamy, L. M., McKay, B. R., Tarnopolsky, M. A., Gibala, M. J., & Parise, G. (2013). Evidence for the contribution of muscle stem cells to nonhypertrophic skeletal muscle remodeling in humans. The FASEB Journal, 27(11), 4596-4605.
20. He, C., Bassik, M. C., Moresi, V., Sun, K., Wei, Y., Zou, Z., … & Levine, B. (2012). Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature, 481(7382), 511-515.
21. Tarnopolsky, M. A., Rennie, C. D., Robertshaw, H. A., Fedak-Tarnopolsky, S. N., Devries, M. C., & Hamadeh, M. J. (2007). Influence of endurance exercise training and sex on intramyocellular lipid and mitochondrial ultrastructure, substrate use, and mitochondrial enzyme activity. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 292(3), R1271-R1278.
22. Joseph, A. M., Adhihetty, P. J., Buford, T. W., Wohlgemuth, S. E., Lees, H. A., Nguyen, L. M., Aranda, J. M., Sandesara, B. D., Pahor, M., Manini, T. M., Marzetti, E., & Leeuwenburgh, C. (2016). The impact of aging on mitochondrial function and biogenesis pathways in skeletal muscle of sedentary high-and low-functioning elderly individuals. Aging Cell, 11(5), 801-809.
23. West, D. W., Burd, N. A., Tang, J. E., Moore, D. R., Staples, A. W., Holwerda, A. M., Baker, S. K., & Phillips, S. M. (2010). Elevations in ostensibly anabolic hormones with resistance exercise enhance neither training-induced muscle hypertrophy nor strength of the elbow flexors. Journal of Applied Physiology, 108(1), 60-67.
24. Nascimento, D. C., Durigan, J. L. Q., Tibana, R. A., Durigan, R. C. Q., Navalta, J. W., & Prestes, J. (2011). The response of matrix metalloproteinase-9 and -2 to exercise. Sports Medicine, 41(11), 921-936.
25. Morton, J. P., Kayani, A. C., McArdle, A., & Drust, B. (2009). The exercise-induced stress response of skeletal muscle, with specific emphasis on humans. Sports Medicine, 39(8), 643-662.
26. Bartolomei, S., Sadres, E., Church, D. D., & Arroyo, E. (2021). Resistance training restores skeletal muscle turnover and proteostasis in an animal model of accelerated aging. The FASEB Journal, 35(3), e21333.
27. Pedersen, B. K., & Febbraio, M. A. (2012). Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nature Reviews Endocrinology, 8(8), 457-465.
28. Safdar, A., Saleem, A., & Tarnopolsky, M. A. (2016). The potential of endurance exercise-derived exosomes to treat metabolic diseases. Nature Reviews Endocrinology, 12(9), 504-517.

*We are currently working on providing full citations, which will be available soon.