The Impact of Progressive Telomere Shortening on Mitochondria Function and Energy Metabolism (2nd year)

Luis Batista, Ph.D.

Project Overview:
Telomeres are found at the ends of our chromosomes and are composed of long stretches of repetitive DNA sequences that are bound to several proteins, which are required to maintain its structure. It has been observed in humans that telomeres become progressively shorter with age. This shortening has been linked to the fact that every time a cell divides, it is unable to replicate the very end of our DNA molecules, the telomeres. Therefore, telomeres get progressively shorter with continuous cellular divisions throughout the human lifetime. When a cell reaches a critical telomere length, after several rounds of division, it becomes unable to divide and dies. Therefore it is not surprising that telomere shortening correlates with loss of tissue function, and that it has been associated with degenerative aging in humans.

We now understand that the correct function of our tissues and organs is extremely dependent on adult stem cells. When these cells divide they are able to both generate a new stem cell, in a process termed self- renewal, and give rise to cells that perform specific functions in any given tissue (a process called differentiation). For instance, hematopoietic stem cells are blood-forming stem cells that are found in the bone marrow and therefore must be viable for the entire life of an individual, giving rise to 1 trillion blood cells every day. It quickly becomes obvious that the maintenance of telomeres above critical length is vital for hematopoietic stem cells and the functioning of the circulatory system. In fact, these cells have a dedicated protein complex that elongates telomeres and maintains their stability, called telomerase.

 

The consequences of not having efficient telomere maintenance would therefore be catastrophic. In fact, several mutations in telomerase have been identified in patients suffering from premature aging syndromes, with phenotypes ranging from bone marrow failure, where hematopoietic stem cells are unable to generate functional blood cells, to liver cirrhosis, where liver cells progressively become replaced by scar tissue. In addition to these “telomere syndromes”, we now understand that telomere erosion is also associated with several diseases of human aging and aging-related processes that occur in our later decades of life. These include cardiovascular diseases, diabetes, cancer and cognitive decline. In fact, telomere erosion is now seen as a disease potentiator and mortality predictor in the elderly. However, the molecular mechanism linking telomere erosion to loss of tissue fitness in the broad elderly population (individuals without genetic mutations in telomerase) is unknown.

 

Research regarding the role of telomere shortening in human lifespan and quality of life has been hampered by a lack of adequate models. To address this issue, we have used genetic engineering (the ability to modify the DNA of cells) to create human pluripotent stem cells with mutations that cause telomere shortening. These cells offer a robust in vitro platform (these cells grow in a dish) to study the consequences of telomere erosion in cells that mimic tissue-renewing cells in humans. During our first year of funding from The Longer Life Foundation we showed that telomere erosion induces profound changes in the function of mitochondria, cellular organelles that are responsible for energy production. Our results for the first time indicate that the mitochondria of human stem cells with short telomeres acquired characteristics of more differentiated, functional cell types. Importantly, mitochondrial dysfunction is considered a hallmark of human aging, being associated with several diseases of the elderly. Thus, we hypothesize telomere dysfunction can serve as a connection between mitochondria dysfunction and loss of stem cell function in aged tissues. This is a novel and provocative idea.

 

In the project we submit for our second year of funding from the LLF, we propose to 1) expand our molecular knowledge on the connection between telomere shortening and mitochondrial biology and 2) understand how this connection affects stem cell function. For this we will directly analyze mitochondrial metabolism in functional, differentiated cells generated from human stem cells with different telomere lengths.

 

In summary, our proposal represents a novel approach on aging research, and successful completion of our aims will significantly increase the current knowledge on the mechanisms leading to increased disease risk in the elderly. This knowledge will be vital for the future development of therapies aiming at increasing the lifespan and quality of life during the later decades of life.