Searching for genetic mechanisms that affect aging - Maria Eriksson
Genetic mechanisms that affect physiological aging are of high interest to society, yet not well understood. The Eriksson research group uses the Hutchinson-Gilford progeria syndrome, or progeria, as a model for their studies on aging.
Most cases of progeria are caused by mutations in the LMNA gene. Children affected by progeria are normal at birth but during their first years of life they start developing multiple symptoms of premature aging - including loss of subcutaneous fat, and hair, reduced bone mineral density and osteoporosis. Most children die in their early teens from complications of cardio-vascular disease, atherosclerosis.
Models of premature aging
which are major proteins of the nuclear lamina. The lamina plays significant roles in replication, transcription, cell division, and chromatin organization. The Eriksson research group use tissue-specific transgenic mice with expression of the most common progeria mutation in skin, aorta, and bone to form models for common diseases with aging. Recent published results from the group showed premature senescence, increased inflammation, early reduction in the pool of adult stem cells and impaired wound healing as a consequence from the expression of the progeria mutation in postnatal epidermis. Expression of the progeria mutation in the bone results in a severe phenotype characterized by loss of osteocytes, increased inflammation, and impaired bone mineralization. Further analysis showed DNA damage and impaired wnt signaling. In addition, the phenotype shows similarities to reported bone abnormalities in aging mice, including distorted organization, and a hypo-cellular bone marrow with prominent white adipocytes. Ongoing studies include the analysis of RNA splicing and intra-individual somatic genetic variation acquired during aging.
Dorsal skin sections were taken from a postnatal day 5 progeriod animal. Although the tight junction layer is functional in the progeriod animals as in the wild-type, the larger exposure area of nucleated cells outside of the tight junction layer, due to epidermal hyperplasia, causes a greater rate of dehydration in progeriod compared to wild-type animals.