Testing a novel hypothesis for a bioenergetic-endocrinological regulation of telomere dynamics
Evolution, Anthropology
Final Report Abstract
It is becoming evident that being healthy and fully functional at old age largely depends on the conditions experienced during the early phases of life. Accumulating evidence suggests that stress experienced during early growth is manifested in the length of telomeres of cells in the body of individuals - complexes of DNA and proteins protect the ends of chromosomes. Telomeres become shorter with progressing age and exposure to stress. The processes that cause telomere shortening, as well as the consequences for the organisms function and Darwinian fitness are still unresolved. One mechanism currently debated is the shortening effect of glucocorticoid hormones on telomeres in both humans and animals. Glucocorticoids like cortisol and corticosterone are vital hormones that keep the organism in energy balance; without their actions organisms would perish in a matter of hours. Thus far, the actions of glucocorticoids on telomeres have been viewed as negative side effects because these hormones can promote cellular oxidative stress and down-regulate the enzyme that maintains TL length, telomerase. However, it is currently unclear how glucocorticoids induce telomere shortening, i.e. whether oxidative stress is the main determinant of glucocorticoid-induced telomere erosion or whether instead metabolic processes also play a role. I am proposing the novel hypothesis that glucocorticoid hormones contribute to regulating telomere length during times of increased energy need by saving resources needed for telomere maintenance. This view is supported by the fact that these hormones can inhibit the enzyme TOR (Target of Rapamycin), a regulator of cell growth, which is directly involved in the control of telomere length. Such a bioenergetical perspective of dynamic telomere regulation through glucocorticoids has never been experimentally examined. I therefore designed a study to test my hypothesis that telomere dynamics depend on an individual’s energy balance in a vertebrate species during early growth, which is an energetically challenging period of life. During a one-year study on free-living great tit (Parus major) nestlings, I manipulated the energetic state of chicks by providing them daily with a standardized oral dose of corticosterone (the glucocorticoid in birds), which is known to increase the metabolic rate of an organism and thus it energy needs. For a different group of nestlings, I improved their nutritional state by providing them with additional nutrients, i.e. oral doses of nucleotides, which are the building blocks of telomeres and therefore potentially a limiting resource during the growth phase in vertebrates. By measuring all chicks and collecting small blood samples before and after the 10 days of the treatment, I monitored their growth, telomere sizes and metabolism, the latter mainly by functional tests of their cell organelles responsible for energy production, the mitochondria. As expected, nestlings receiving extra glucocorticoids had shorter telomeres, a higher metabolic rate (i.e. a higher amount of oxygen was consumed by their mitochondria), but a lower mitochondrial efficiency. A low mitochondrial efficiency was evidenced by the finding that less cellular energy was produced per amount of oxygen consumed, a phenomenon called 'proton leak'. However, proton leak was not the only cause of short telomeres because mitochondrial efficiency was also reduced in nestlings that did not show short telomeres. It is possible that a combination of high metabolic rate and high proton leak activated some physiological pathways that could have led to shorten telomere sizes. Cellular oxidative stress was not altered by glucocorticoid administration, suggesting that these processes may not directly affect telomere length. As predicted, nestlings receiving extra nucleotides had longer telomeres than any other group. This is in line with my novel hypothesis that an increased availability of nucleotides would attenuate telomere erosion during energy-demanding growth phase. Similarly, nestlings that were supplemented with both nucleotides and glucocorticoids at the same time did not have shorter telomeres indicating that nucleotides were able to neutralize the eroding effect of glucocorticoids on telomeres. Thus far, these findings support the novel hypothesis that telomeres can be regulated depending on the energetic state of the organism. I have begun to test this explanation through analyses of the expression of metabolic genes regulated by TOR and analyses are still in progress.
Publications
- Baseline glucocorticoids increase mitochondrial metabolic rate in wild great tit nestlings. International Ornithological Congress (IOC), Vancouver 19-26 August 2018
Casagrande S., Stier, A., Hau, M.
- 2019. Telomere attrition: metabolic regulation and signalling function?
Biology Letters, Vol. 15. 2019, Issue 3, 20180885.
Casagrande, S. and Hau, M.
(See online at https://doi.org/10.1098/rsbl.2018.0885) - 2020. Increased glucocorticoid concentrations in early life cause mitochondrial
inefficiency and short telomeres. Journal of Experimental Biology, Vol. 223. 2020, Issue 15, 222513.
Casagrande, S., Stier, A., Monaghan, P., Loveland, J.L., Boner, W., Lupi, S., Trevisi, R., & Hau, M.
(See online at https://doi.org/10.1242/jeb.222513)
