Modeling Human Aging in a Dish
By 2040, there will be 1.3 billion individuals age 65 or older in the world; most of them will suffer from various aging-associated diseases such as cardiovascular diseases, neurodegenerative diseases, diabetes, and cancer. Although various model organisms have been employed to study the mechanism of aging, we are still lacking appropriate strategies (e.g. cell models) to study human aging and age-related human diseases efficiently. Recently, increasing evidence has shown that aging human cells are associated with marked alterations in nuclear lamina. Single-site mutations of lamin A, the main structural component of nuclear lamina in somatic cells, can result in a group of human premature aging diseases called "progerias" (eg. Hutchinson-Gilford Progeria Syndrome (HGPS) and Atypical Werner Syndrome (AWS) etc). HGPS is caused by constitutive production of progerin, a splicing mutant of lamin A. Accumulation of progerin in cells can result in various age-related nuclear defects, including loss of heterochromatin marks, increased DNA damage, and telomere attrition. The causes of death in progeria patients are chronic conditions commonly found in elderly people, such as atherosclerosis and stroke. Striking similarities between physiological aging and progeria syndrome have been reported. Interestingly, progerin is also found in normal vascular cells, which increases in amount by ~3% per year. Recent studies have suggested that progerin appears to cooperate with telomere dysfunction to control aging process. Thus, progerin accumulation could well be not only an important marker but also a promoter for physiological aging. Studying the pathogenesis of premature aging may represent an important way to gain insights into normal aging and age-associated diseases.
Induced Pluripotent Stem cell (iPSC) technology opens an unprecedented avenue to model human diseases in a dish. Patient-specific fibroblasts bearing the disease mutations can be clinically isolated and reprogrammed into a pluripotent status with the capability to differentiate into various cell types in vitro. By reprogramming the fibroblasts obtained from the patients with premature aging syndromes, we wish to understand:
1) The molecular process of dedifferentiation of aging cells.
2) How reprogramming resets the cellular context of aging cells.
3) How to employ/optimize in vitro differentiation / culture system to recapitulate the phenotypes observed in premature aging individuals.
4) The cellular and molecular mechanism of human premature aging and physiological aging.
5) The potential molecular targets for anti-aging drugs.
Recently, increasing evidence indicates that genetic defects observed in patient somatic cells could be erased/or alleviated by direct reprogramming towards pluripotency and recapitulated upon directed differentiation to specific cell lineages. More specifically, we have recently described an iPS aging model that faithfully recapitulates physiological aging and senescence in vitro. However, these patient derived-iPSCs lack the proper isogenic controls and might not represent the “gold standard” for disease modeling. With the advent of the development of gene-editing technologies suitable for gene-targeting in human pluripotent cells not only isogenic "corrected" iPSCs have been generated but also "disease-specific" Embryonic Stem Cells (ESCs) have been described. The genetic correction of monogenic mutations responsible for the development of disease and generation of isogenic iPSCs lines may not only contribute for more reliable experimental control sets but also brings the opportunity for combining gene therapy and regenerative medicine in novel therapeutic treatments. Our goals are to first develop and standardize efficient protocols for the generation of patient-derived induced pluripotent stem cells (iPSCs) and their corresponding isogenic lines by specific manipulation of selected loci related to aging. Our long-term goals involve using patient derived-iPSC as cellular models to investigate how human genetic variation influences gene regulatory networks and protein function involved in aging and aging-associated development of disease. Moreover, we are currently exploring the use of our aging models for drug discovery studies affecting physiological aging. Such results could eventually translate into the development of therapies contributing to "healthy" aging and perhaps, even getting us closer to one of the most common human dreams, "the eternal youth fountain".