Chapter 180
Changing Aging — 17
On the other hand, a high-fat or ketogenic diet, particularly on a long-term basis, has been linked to accelerated aging in mice and humans, reflected by increased cellular senescence. Changes in the gut microbiome, and specifically an increase in the species of Desulovibrio bacteria, was found after a high-fat diet in mice with markedly increased leucine production. High blood leucine was also seen in women with breast cancer with poor clinical outcomes. Experiments to untangle the high-fat diet and changes in gut microbiome revealed that leucine signaled the bone marrow to activate white cell suppressor cells, the mTOR pathway, and to promote tumor progression. Collectively, these findings and the adverse cardiovascular effects summarized in chapter 3 suggest that we should avoid long-term ketogenic diets.
While there are no dietary supplements that have been shown to promote health span, there is one good candidate—taurine. Taurine levels in people decline with age, and deficiency has been correlated with higher levels of inflammation and age-related diseases. Supplementation promoted health span in monkeys and reduced cellular senescence, inflammaging, and mitochondrial dysfunction. We await randomized trials to verify the effects in animal models.
Exercise has impressive effects for extending health span. Less inflammation, a fortified immune response, less atherosclerosis, better insulin sensitivity and less metabolic syndrome and type 2 diabetes, and a reduction in incidence of many cancers have consistently been seen in multiple reports. In a large study of more than 650,000 individuals aged twenty-one to ninety, with ten years of follow-up, a substantial gain in lifespan was seen with increasing metabolic equivalent hours per week (MET-hr/wk) of physical activity (fig. 12.7). Compared with no physical activity, this equated to about 4.5 years of life gained linked with 450 minutes of walking each week.
Figure 12.7. Relationship between physical activity and years of life gained. Adapted from Steven Moore et al., “Leisure time physical activity of moderate to vigorous intensity and mortality: A large pooled cohort analysis,” PLOS Medicine 9, no. 11 (2012): e1001335, https://doi.org/10.1371/journal.pmed.1001335.
As Steve Horvath and I reviewed, exercise is the only well-validated intervention to reset biological age in humans (fig. 12.8). Some of the salutary effects of exercise can be attributed to exerkines—the multiplicity of compounds that are released. While some of these tone down inflammation, like interleukin-10, others, like interleukin-6, can increase with high intensity and long duration, which simulates the stress response, an adaptive preconditioning for the real thing. An example is the immune response from one hour of aerobic and strength exercise in people with pancreatic cancer: not only a significant jump in CD8+ cytotoxic T cells but with a doubling of survival time for these cells to help fight the cancer. A big exercise NIH research Molecular Transducers of Physical Activity Consortium initiative began in 2016 in both animal models and more than twenty-five hundred people. Findings from the multiomic study of rats with treadmill training over eight weeks showed better mitochondrial function, less inflammation, likely reduction of autoimmune disease such as inflammatory bowel disease, and protection from fatty liver disease. In a separate experimental study, rejuvenation of skeletal muscle stem cells in old mice was achieved by exercise.