Abstract
Aging, a time-dependent functional decline of biological processes, is the primary risk factor in developing diseases such as cancer, cardiovascular or degenerative diseases. There is a real need to understand the human aging process in order to increase the length of disease-free life, also known as "health span". Accumulation of progerin and prelamin A are the hallmark of a group of premature aging diseases but have also been found during normal cellular aging strongly suggesting similar mechanisms between healthy aging and LMNA-linked progeroid syndromes. How this toxic accumulation contributes to aging (physiological or pathological) remains unclear. Since affected tissues in age-associated disorders and in pathological aging are mainly of mesenchymal origin we propose a model of human aging based on mesenchymal stem cells (hMSCs) which accumulate prelamin A. We demonstrate that prelamin A-accumulating hMSCs have a premature aging phenotype which affects their functional competence in vivo. The combination of prelamin A accumulation and stress conditions enhance the aging phenotype by dysregulating the activity of the octamer binding protein Oct-1This experimental model has been fundamental to identify a new role for Oct-1 in hMSCs aging.
Highlights
Aging, the major risk factor in developing many chronic conditions is characterized by deterioration in the maintenance of homeostatic processes over time, leading to functional decline, with a consequent increased risk for disease and death
To assess whether we could take advantage of this system as an experimental model of human cellular aging, we challenged prelamin AhMSCs to recapitulate other hallmarks of aging recently proposed by Lopez-Otín and collaborators [24]
We observed in each donor a decline in mean telomere length of prelamin A-human aging based on mesenchymal stem cells (hMSCs) when compared to the controls cells, a change which was statistically significant in three samples (640 bp loss in 18 year old donor, 400 bp loss in 25 year old donor, 380 bp loss in 58 year old donor)
Summary
The major risk factor in developing many chronic conditions is characterized by deterioration in the maintenance of homeostatic processes over time, leading to functional decline, with a consequent increased risk for disease and death. Alteration of the nuclear lamina, one of the cellular changes observed in physiological aging [1] [2], is the hallmark of a group of premature aging diseases known as progeroid laminopathies These diseases, such as Hutchinson-Gilford Progeria syndrome (HGPS) or LMNA-linked lipodystrophy are caused by mutations in LMNA gene which encode several isoforms of A-type lamins, being among them Lamin A protein [3, 4], or in FACE1/Zmpste gene which encode a protease essential for the normal processing of Lamin A protein [5]. In the case of HGPS or LMNA-linked lipodystrophy, the affected tissues are mainly of mesenchymal origin [8] suggesting that the cell-type specific pathologies in aging could be due, in part, to mesenchymal stem cell (hMSCs) exhaustion or mesenchymal lineage differentiation defects [9, 10, 11]
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