Current Pharmaceutical Design - Volume 19, Issue 9, 2013

The biological bases of cellular and organismal aging are thought to involve, among others, basic stress response mechanisms. In this field an increasing amount of evidence, in recent years, point towards an important role of endogenous retroelements. During evolution these mobile genetic elements interpreted the dual role of selfish genomic parasites and useful “boosters” of genomic evolution. Similarly, in living cell these elements have an important role in stress response and in generating neuronal plasticity, but studies on in vitro cell cultures and animal models show that their excessive activation or misregulation may lead to DNA damage and cell senescence, and can trigger both innate immunity and a pro-inflammatory response. Being cell senescence, somatic DNA damage and inflammation three supposed key processes in human aging, and observing that several intracellular mechanisms normally controlling the activation of retroelements show a tendency to fade at late ages, a possible role of endogenous retroelements in organismal senescence is taken in consideration. A better knowledge of the basic mechanisms linking stress response, activation of endogenous retroelements and age-related cell/tissue alterations could not only help us gain a better understanding of the basic mechanisms of aging, but will also allow the experimentation of new therapeutic targets for different age-related diseases.

In ageing, the accumulation of damaged molecules provoked by oxidative stress and inflammation contributes to altered gene expressions and cellular dysfunction. The antioxidant system is crucial in order to prevent damage to intracellular molecules including DNA and, consequently, to avoid cellular dysfunction or neoplastic transformation. However, during serious DNA damage, the cells can activate a response characterized by cell cycle arrest and production of factors (mainly chemokines and cytokines) named “senescent associated secretory phenotype” (SASP) with the putative function to attract immune cells involved in the clearance of the senescent cells. This phenomenon named “cellular senescence” is, by one side, an important tumor suppressive mechanism but, on the other side, it contributes to impair tissue regenerative capacity and to possible transformation of neighbouring cells to cancer cells if a rapid clearance of the senescent cell doesn’t occur. Therefore, preventing DNA damage via an optimal intracellular antioxidant defence is the key to reduce risk of cancer while keeping senescent changes at minimum. Zinc-bound Metallothioneins (MT), could play a key role in this prevention because they are antioxidant proteins and release zinc ions for several proteins and enzymes involved in antioxidant and DNA-repair responses. Reduced MT expression and intracellular zinc occur in some models of senescent cells. This process is of relevance since zinc ions released from MT could be implicated in the modulation of SASP. In chronic inflammation, such as in ageing, the dysfunction in zinc release from MT occurs, suggesting a potential contribution to the onset of senescent cells. Hence, MT could be directly or indirectly involved in the modulation of cellular senescent state and might represent a possible therapeutic target against the accumulation of dysfunctional senescent cells.