Pharmacogenetics and pharmagenomics, trends in normal and pathological aging studies: focus on p53.
In spite of the fact that the aging organism is the result of complex life-long gene/environment interactions, making peculiar the susceptibility to diseases and the response to drugs, pharmacogenetics studies are largely neglected in the aged. Altered response to drugs, cardiovascular and metabolic alterations, cancer and dementia are among the age associated ailments. The latter two are the major contributors to illness burden for the aged. Aging, dementia and cancer share a critical set of altered cellular functions in the response to DNA damage, genotoxic stress, and other insults. Aging in higher animals may be influenced by the balance of cell survival versus death, a decision often governed by checkpoint proteins in dividing cells. The paper is mainly focused on one of such proteins, p53 which has been recently shown to be involved in aging and Alzheimer's Disease (AD). Within this reference frame we studied p53 in aged controls and demented patients finding that with aging there is an increase of mutant like conformation state of p53 in peripheral blood cells, which is more pronounced in AD patients. As a result of such conformational change, p53 partially loses its activity and may become unable to properly activate an apoptotic program when cells are exposed to a noxious stimulus. Moreover we found that the tertiary structure of p53 and the sensitivity to p53-dependent apoptosis are affected by low concentrations of soluble beta amyloid, the peptide that accumulates in AD brain but also present in peripheral tissues. It is possible that p53 conformers may occur in the presence of misfolded molecules such as, but not limited to, beta amyloid. In particular at neuronal level the altered function of cell cycle proteins may affect synaptic plasticity rather than cell duplication.
Lanni
C
C
Department of Experimental and Applied Pharmacology, University of Pavia, Viale Taramelli 14, 27100 Pavia, Italy.
Racchi
M
M
Uberti
D
D
Mazzini
G
G
Stanga
S
S
Sinforiani
E
E
Memo
M
M
Govoni
S
S
D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation; D009473:Neuronal Plasticity; D010597:Pharmacogenetics; D017434:Protein Structure, Tertiary; D013569:Synapses / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016159:Tumor Suppressor Protein p53