Activation of telomerase can rejuvenate animals

The majority of somatic cells do not express telomerase and consequently become senescent when telomeres reach a critically short length. Therefore, one of the potential strategies to rejuvenate the body would be to extend the telomeres of somatic cells by reactivating telomerase. Jaskelioff et al¹⁴ explored the hypothesis of rejuvenation by engineering a knock-in allele, encoding an inducible telomerase reverse transcriptase in a transgenic mice line. Homozygous transgenic mice displayed short dysfunctional telomeres, while the gene was not induced. These transgenic mice showed dramatically premature ageing phenotypes such as greying of the hair and osteoporosis, as well as atrophy of testes, spleen, small intestine and brain. Surprisingly, all ageing phenotypes shown in the transgenic mice were reversed when their telomeres were re-lengthened by reactivating telomerase. Intriguingly, they found that the atrophied brain shown in transgenic mice returned to normal size following telomerase reactivation. An electron microscopic study of brain white matter showed that decreased myelination in axonal tract of corpus callosum in association with oligodendrocyte deficiency observed in these mice was completely recovered and comparable to younger mice, suggesting that telomerase reactivation ameliorated the function and number of oligodendrocytes in the brain of transgenic mice.

They also looked into the biological activity of neuronal precursor cells by quantitative FISH analysis, revealing that telomere elongation in neuronal precursor cells resulted in the preservation of neural progenitor reserves and their neurogenic capacity in vivo¹⁴. The experiment clearly demonstrated the possibility that telomerase reactivation in somatic cells can reverse tissue atrophy, stem cell depletion, and organ system failure as well as impaired tissue injury responses associated with age-related diseases such as senile dementia, osteoporosis, and sarcopenia.

Lifestyles and stress are associated with telomere length

Recently, Ornish et al¹⁵ reported that 30 men with biopsy-diagnosed low-risk prostate cancer with 3 months of comprehensive lifestyle intervention showed an 29.84% increase of telomerase activity with associated decrease of LDL cholesterol and psychological stress. The lifestyle intervention in this study included low-fat whole foods, and a plant-based diet high in fruit, vegetables, unrefined grains, and legumes, as well as moderate aerobic exercise and stress management with gentle yoga-based stretching, breathing, meditation, imagery, and progressive relaxation techniques with 1 hour of group support sessions.

The fact that telomerase activities can be up-regulated by lifestyle changes is consistent with previous studies showing the decrease of telomerase activity in response to life stress¹⁶. People who are stressed over long periods tend to look haggard so that it is commonly thought that psychological stress leads to premature ageing, as well as earlier onset of age-related diseases such as osteoporosis, cardiovascular diseases, and cancers. Epel et al¹⁶ found that caregivers with chronic psychological stress showed higher oxidative stress, lower telomerase activity, and shorter telomere length, which are known determinants of cell senescence and longevity; suggesting the possibility that psychological stress induces cellular oxidative stress that suppresses telomerase activity with concomitant telomere shortening. Intensive lifestyle changes and stress reduction are also beneficial for coronary heart disease patients.

In another study, Ornish et al¹⁷ reported that intensive lifestyle changes significantly improved the stenotic lesions diagnosed by coronary angiography in coronary artery disease patients with arterial stenosis after 5-year follow-up. In this study, the average diameter stenosis of the coronary artery was widened by 3.1% after 5 years of intervention, while the stenosis was further narrowed by 11.8% after 5 years of observation in a control group. Since telomeres play a pathological role in the progression of atherosclerosis¹⁸, lifestyle changes may help to protect telomeres in coronary endothelial cells with concomitant regression of atherosclerosis. In these pathological sections, the arterial segments that did not develop atherosclerosis, such as the internal mammary artery, had longer telomeres than aortic segments with atherosclerosis in situ¹⁸.

Telomeres and stem cells

It is known that telomerase is specifically expressed in stem cells, germ line cells, and cancer cells, but not in somatic cells². Therefore, the telomerase activity of peripheral blood mononuclear cells (PBMCs) in Ornish’s studies^15,17 may attribute to the telomerase activity from circulating stem cells in the peripheral blood, but not from cancer cells because no increase of prostate‑specific antigen (PSA) has been found in prostate cancer patients with lifestyle intervention¹⁵. Also interesting to speculate is that lifestyle changes such as smoking cessation increase the number of circulating stem cells in the peripheral blood. In fact, Kondo et al¹⁹ demonstrated that the number of circulating endothelial progenitor cells is reduced in chronic smokers, but rapidly recovered after smoking cessation, and almost doubled after 4 weeks. The association between cigarette smoking and the suppression of circulating progenitor cells supports the report that telomeres of PBMCs of smoking women are shorter than those of non-smoking women²⁰. This data suggests the possibility that some substances contained in cigarettes inactivate the generation of progenitor cells, or alternatively suppress the progenitor cells from migrating into the blood circulation.

Somatic stem cells are present throughout the body, including brain, bone marrow, blood, blood vessels, skeletal muscles, skin, and liver. Biologically, somatic stem cells play an important role in the maintenance and regeneration of tissues and organs of the body. Therefore, ageing of somatic stem cells evokes the degenerative pathologies of age-related diseases such as atherosclerosis, senile dementia, brain atrophy, sarcopenia, immune deficiency, and wrinkles in
the skin.

Perceived age — the evaluation of age by the appearance of a person — is negatively influenced by exposure to sun, smoking and low body mass index (BMI), and positively influenced by high social status, low depressive state and marital status²¹. From the pathological and clinical points of view, somatic stem cells are closely associated with ageing phenotypes of skin, hair, adipose tissue, blood vessels, muscles and brain. A decrease of epithelial stem cells causes thinning of the skin and winkles, while the decrease of mesenchymal stem cells in adipose tissue and connective tissue causes the lose of elasticity in the skin.

Intriguingly, Christensen et al¹¹ reported that telomere length is the only biomarker that predicts perceived age base on the cohort study of 1826 twins older than 70 years of age¹¹. Since stem cells are subjected to
age, telomere maintenance of stem cells may be a pivotal molecular mechanism that regulates the regenerating capacity in various tissues of the body, eventually conferring a younger phenotype, as well as a younger perceived age. So, one of the strategies to stay young when one gets old is to activate telomerase activity of somatic stem cells and maintain the number of stem cells in the tissues so that the body retains
the regenerative capacity, as well as resistance to degenerative diseases and the ability to exhibit
younger phenotypes.

Conclusions

In summary, telomeres are a useful biomarker for the future research of both anti-ageing and preventive medicine. Telomere measurement can also be applied for the evaluation of lifestyle intervention, pharmaceutical intervention, and nutraceutical intervention for lifespan extension.