Title:Metallothioneins, Ageing and Cellular Senescence: A Future Therapeutic Target
Volume: 19
Issue: 9
Author(s): Eugenio Mocchegiani, Laura Costarelli, Andrea Basso, Robertina Giacconi, Francesco Piacenza and Marco Malavolta
Affiliation:
Keywords:
Metallothioneins, ageing, cellular senescence, inflammation, MT-target therapeutic approach, cellular dysfunction, antioxidant system, cancer, chemokines, cytokines
Abstract: 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.
