Normal human breast epithelial cells were transfected with expression vectors containing the p53 gene mutated at either codon 143, 175, 248 or 273, or by infection with a recombinant retroviral vector containing the p53 gene mutated at codons 143, 175, 248, or 273. The breast epithelial cells were monitored for extension of in vitro lifespan and immortalization. Expression of some, but not all, p53 mutants resulted in an extension of in vitro lifespan.
Replicative senescence is thought to be a significant barrier to human tumorigenesis, which in human fibroblasts, and many other cell types, can be overcome experimentally by combined loss of function of p53 and Rb 'pathways'. To avoid the confounding pleiotropic effects of HPVE7 frequently used in such studies, here we have employed retroviral vectors over-expressing CDK4 or CDK6 as a more representative model of naturally-occurring mutations targeting the Rb pathway.
Centenarians are people who escaped from major common diseases, including cancer, and reached the extreme limits of human life-span. The analysis of demographic data indicates that cancer incidence and mortality show a levelling off around the age of 85-90 years, and suggests that oldest old people and centenarians are protected from cancer onset and progression.
A naturally occurring p53 isoform that lacks 39 residues at the N-terminus (denoted ?Np53), when expressed with wild-type p53 (WTp53), forms mixed ?Np53:WTp53 tetramers and causes accelerated aging in mice. Cellular alterations specific to ?Np53:WTp53 have been difficult to assess because ?Np53 and WTp53 coexpression results in tetramer heterogeneity, including formation of contaminating WTp53 tetramers. Based on the p53 tetramer structure, we expressed ?Np53 and WTp53 as a single transcript that maintained tetramer architecture, ensuring a 2:2 ?Np53:WTp53 stoichiometry.
Recent results indicate that the longevity of both invertebrates and vertebrates can be altered through genetic manipulation and pharmacological intervention. Most of these interventions involve alterations of one or more of the following: insulin/IGF-I signaling pathway, caloric intake, stress resistance and nuclear structure. How longevity regulation relates to aging per se is less clear, but longevity increases are usually accompanied by extended periods of good health. How these results will translate to primate aging and longevity remains to be shown.
Telomeres are elongated by the enzyme telomerase, which contains a template-bearing RNA (TER or TERC) and a protein reverse transcriptase. Overexpression of a particular mutant human TER with a mutated template sequence (MT-hTer-47A) in telomerase-positive cancer cells causes incorporation of mutant telomeric sequences, telomere uncapping, and initiation of a DNA damage response, ultimately resulting in cell growth inhibition and apoptosis. The DNA damage pathways underlying these cellular effects are not well understood.
Ashwagandha, also called as "Queen of Ayurveda" and "Indian ginseng", is a commonly used plant in Indian traditional medicine, Ayurveda. Its roots have been used as herb remedy to treat a variety of ailments and to promote general wellness. However, scientific evidence to its effects is limited to only a small number of studies. We had previously identified anti-cancer activity in the leaf extract (i-Extract) of Ashwagandha and demonstrated withanone as a cancer inhibitory factor (i-Factor).
Evidence has accumulated from laboratory-based animal experiments and population-based human epidemiological studies that lifestyle factors that affect energy balance, such as caloric intake, nutritional status, and exercise, act in concert with genetic susceptibility to influence cancer development and progression.