Cellular senescence in pharmacogerontology research

The administration of pharmacological agents to older persons often results in a higher incidence of drug toxicity and adverse drug reactions compared with the young. This is mainly due to changes in pharmacokinetic (the process by which a drug is absorbed distributed, metabolised, and eliminated by the body) and pharmacodynamic (what a drug does to the body) properties believed to be the result of biological alterations linked to the ageing process. Therefore, understanding the mechanisms of ageing, the biological alterations they bring about and the biological consequence of such alterations could help answer questions concerning the pharmacokinetic and pharmacodynamic changes observed in the elderly.

The pharmacokinetic changes observed in elderly patients are well understood (click here) and allowances can be made for them. However, pharmacodynamic’s is much harder to predict as it requires an understanding of the biological changes associated with ageing (many of which may be individual specific). Insight into these processes has mainly been generated by laboratories focused on the molecular mechanism underlying the ageing process. These groups often have a limited understanding of the pharmacology of the elderly. Therefore, research in this area appears not to have progressed beyond cataloguing the observed drug responses in the elderly.

The accumulation of senescent cells in tissues has been linked to ageing and disease and as such could potentially alter the biological response to drugs in the elderly. When a cell becomes senescent, it undergoes a radically altered phenotype (click here). Microarray analysis of primary human lung fibroblasts (IMR-90) and primary skin fibroblasts (Detroit 551) reported that of the 4183 genes analysed, 165 were down-regulated and 191 up-regulated in senescent IMR-90 cells and 154 down-regulated and 76 up-regulated in senescent Detroit 551 cells compared with their growing counterparts (Chen et al 2004). This degree of alteration in the transcriptome is akin to that seen when cells are induced to differentiate (Truckenmiller et al 2001). Essentially, senescent cells should be treated as a completely different cell type from when they were growth competent. Therefore, more research should be carried to determine whether or not senescent cells display an altered responsiveness to pharmacological agents.


By bridging the gap between pharmacokinetic and pharmacodynamic studies and molecular gerontology it is hoped that pharmaceutical intervention might one day be more precisely targeted to the age of the patient (and thus, the biological status of the target tissue). It is anticipated that the development of in-vivo and in-vitro models of tissue ageing will facilitate the necessary advances in pharmacogerontology.

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The main focus of ageing research is to prevent/combat age-related disease and disability, allowing everyone to live healthier lives for longer.