Carpe Vitae

Life expectancy, healthspan & DNA repair

Global average life expectancy has increased by more than 10 years over the last four decades. With this, the prevalence and cost of treating age-related diseases has risen exponentially. On average, people across the globe will lose around nine years of healthy life because of age-related diseases and disability — reducing the amount of time spent living life to the fullest.

Age is an independent risk factor for many of the diseases we encounter as we grow older. This is due to a reduction in our bodies’ natural ability to repair DNA damage as we age — leading to the development of cancer and other illnesses. Cellular DNA repair processes can protect us from the accumulation of DNA damage; however, these repair pathways also decline in efficiency and accuracy as we age. The accumulation of DNA damage and genome instability is also linked with ageing-associated diseases, highlighting the importance of DNA repair in the prevention of these disorders. Mutations in genes leading to premature ageing/progeria syndromes are also associated with DNA repair.

DNA contains the “master instruction book” for our cells to make the proteins that control the majority of processes in our bodies. As such, the accuracy of our DNA sequences is crucial for the correct functioning of our cells and organs, and our health overall. Our cells experience DNA damage multiple times a day by external (exogenous) factors like ultraviolet radiation from the sun; and internal (endogenous) processes such as DNA replication errors. DNA damage affects all aspects of cell biology, including disruption of DNA structure, gene expression and metabolic functions. Persistent DNA damage also leads to the activation of cellular senescence pathways which repress cell cycle progression to prevent the replication of damaged DNA. Senescent cells have a negative effect on surrounding cells, through the secretion of pro-inflammatory chemicals, leading to inflammation in the affected tissue. This DNA damage-dependent loss of cellular function, cell death and senescence-induced tissue inflammation has been suggested to drive the ageing process, leading to ageing-related diseases such as osteoporosis, cancer, neurodegenerative diseases including Alzheimer’s disease, non-alcoholic fatty liver disease, atherosclerosis, and other ageing-related conditions.

By utilising our profound expertise in DNA damage repair to develop ground-breaking products and solutions, we strive to prevent unnecessary ageing and drastically improve the number and quality of healthy years — not only to revolutionise global health care, but also to completely transform how we live.

Akazawa, Y., Nakashima, R., Matsuda, K., Okamaoto, K., Hirano, R., Kawasaki, H., et al. (2019). Detection of DNA damage response in nonalcoholic fatty liver disease via p53-binding protein 1 nuclear expression. Mod Pathol 32(7), 997-1007. doi: 10.1038/s41379-019-0218-8.

Alimirah, F., Pulido, T., Valdovinos, A., Alptekin, S., Chang, E., Jones, E., et al. (2020). Cellular Senescence Promotes Skin Carcinogenesis through p38MAPK and p44/42MAPK Signaling. Cancer Res 80(17), 3606-3619. doi: 10.1158/0008-5472.CAN-20-0108.

Australian Institute of Health and Welfare 2021. Australian Burden of Disease Study 2018: key findings. Australian Burden of Disease Study series 24. Cat. no. BOD 30. Canberra: AIHW.

Barranco, C. (2018). Atherosclerosis linked to faulty DNA repair in VSMCs. Nat Rev Cardiol 15(7), 380. doi: 10.1038/s41569-018-0021-0.

Chandra, A., Lagnado, A.B., Farr, J.N., Monroe, D.G., Park, S., Hachfeld, C., et al. (2020). Targeted Reduction of Senescent Cell Burden Alleviates Focal Radiotherapy-Related Bone Loss. J Bone Miner Res 35(6), 1119-1131. doi: 10.1002/jbmr.3978.

Chen, Q., Liu, K., Robinson, A.R., Clauson, C.L., Blair, H.C., Robbins, P.D., et al. (2013). DNA damage drives accelerated bone aging via an NF-kappaB-dependent mechanism. J Bone Miner Res 28(5), 1214-1228. doi: 10.1002/jbmr.1851.

Coppe, J.P., Patil, C.K., Rodier, F., Sun, Y., Munoz, D.P., Goldstein, J., et al. (2008). Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 6(12), 2853-2868. doi: 10.1371/journal.pbio.0060301.

Coppede, F., and Migliore, L. (2015). DNA damage in neurodegenerative diseases. Mutat Res 776, 84-97. doi: 10.1016/j.mrfmmm.2014.11.010.

Hoeijmakers, J.H. (2009). DNA damage, aging, and cancer. N Engl J Med 361(15), 1475-1485. doi: 10.1056/NEJMra0804615.

Kirkland, J.L., and Tchkonia, T. (2020). Senolytic drugs: from discovery to translation. J Intern Med 288(5), 518-536. doi: 10.1111/joim.13141.

Ogrodnik, M., Miwa, S., Tchkonia, T., Tiniakos, D., Wilson, C.L., Lahat, A., et al. (2017). Cellular senescence drives age-dependent hepatic steatosis. Nat Commun 8, 15691. doi: 10.1038/ncomms15691.

Partridge, L., Deelen, J., and Slagboom, P.E. (2018). Facing up to the global challenges of ageing. Nature 561(7721), 45-56. doi: 10.1038/s41586-018-0457-8.

Roos, C.M., Zhang, B., Palmer, A.K., Ogrodnik, M.B., Pirtskhalava, T., Thalji, N.M., et al. (2016). Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell 15(5), 973-977. doi: 10.1111/acel.12458.

Schumacher, B., Pothof, J., Vijg, J., and Hoeijmakers, J.H.J. (2021). The central role of DNA damage in the ageing process. Nature 592(7856), 695-703. doi: 10.1038/s41586-021-03307-7.

Scott, A.J., Ellison, M. & Sinclair, D.A. The economic value of targeting aging. Nat Aging 1, 616–623 (2021).

Yousefzadeh, M., Henpita, C., Vyas, R., Soto-Palma, C., Robbins, P., and Niedernhofer, L. (2021). DNA damage-how and why we age? Elife 10. doi: 10.7554/eLife.62852.

Zhang, P., Kishimoto, Y., Grammatikakis, I., Gottimukkala, K., Cutler, R.G., Zhang, S., et al. (2019). Senolytic therapy alleviates Abeta-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat Neurosci 22(5), 719-728. doi: 10.1038/s41593-019-0372-9.