The role of TELOmeres in POST-mitotic cell functioning and ageing – TELOPOST

Extension of life expectancy is considered to be one of the best indicators of the quality of any healthcare system. However, aging increases healthcare costs because the prevalence of age-associated diseases rises. Therefore, a major effort has been made over the last 50 years to better understand aging-associated pathways and to promote health in the elderly. From a biological perspective, ageing is characterized by the overall decline in maintaining tissue homeostasis and responding to physiological stress. At the cellular level, the accumulation in tissues of senescent cells (permanent cell cycle arrest) emerges as a key driver of aging. Consistently, senescent cells can be found in the affected tissues of patients with age-related diseases such as osteoarthritis, pulmonary fibrosis and atherosclerosis. Conversely, recent data show that senescent cell elimination in healthy animals prolongs healthy lifespan.
However, some cells can progressively loose their functional capacities with age without exhibiting any clear sign of senescence. This is for instance the case of long-lived post-mitotic cells (collectively named LLPMCs), such as myofibers and neurons, which can live for decades in the organism. For these cells, it is generally accepted that the age-dependent increased production of reactive oxygen species (ROS) due to dysfunctional mitochondria, coupled with the inherent inability of autophagy and other cellular-degradation mechanisms to remove damaged molecules, are responsible for their progressive decline. However, the age-dependent mechanisms (aging clock) that lead to these cellular changes and the link between this LLPMC aging process and the “classical” cellular senescence pathways remain largely unknown.

Among the ageing hallmarks, the instability and dynamics of telomeres act as a mitotic clock of cellular senescence. However, evidence for changes in telomeres during LLPMC aging remains limited. Based on a series of published and unpublished groundbreaking recent findings, we built an unique consortium of four teams with complementary expertise in telomere, muscle and neuron biology to propose an highly integrated, cross-disciplinary and innovative research program, named TELOPOST, to address the following question: do telomeres play a role in long-lived post-mitotic cell functioning and aging?

We believe that the knowledge that will be acquired through TELOPOST will be of paramount importance to our understanding of what cell aging means in healthy and pathological situations. Preserving muscle and neuronal functions in the elderly constitute public health challenges to improve elderly life quality and longevity. Alterations in any of the processes are implicated in the pathological dysfunctions of sarcopenia, myopathies, and neuro-degenerative illnesses. Thus, the experimental results of TELOPOST will contribute to developing new therapies for age-related diseases such as neurodegenerative pathologies and sarcopenia and new diagnostic tools for frailty in aging patients, and is expected to lead to innovative industrial ventures and start-ups based on the development of cellular aging biomarkers and pharmacological agents to delay and cure age-related pathologies.

Overall, TELOPOST will boast several original and novel features on the role of telomeres in aging:
- the concept that telomere dysfunction drives post-mitotic cell aging;
- methods, because it will develop new assays, mouse models and biomarkers to study post-mitotic cell aging and telomere-driven aging;
- societal implications, by identifying mechanisms delaying aging;
- economical and medical implications, by providing new biomarkers and pharmacological target to prevent and cure age-related pathologies.