Nucleoside reverse transcriptase inhibitors as a therapeutic opportunity to counteract inflammaging and age-related diseases: New evidence from epidemiological data

Nucleoside Reverse Transcriptase Inhibitors (NRTIs), widely used to treat HIV and hepatitis B, have recently been shown to possess anti-inflammatory properties by inhibiting inflammasome activation. Epidemiological studies have revealed a significantly reduced incidence of age-related diseases, such as Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM), among patients chronically treated with NRTIs, but not with other classes of antiretroviral drugs. In this short review, we explore the mechanistic and clinical evidence linking NRTIs to reduced inflammaging, with particular attention to their effects on endogenous retroelements such as LINEs, SINEs and human endogenous retroviruses (HERVs). These elements, increasingly active with age, contribute to sterile inflammation and disease progression. NRTIs may mitigate this process by blocking reverse transcriptase-dependent formation of RNA:DNA hybrids and other immunostimulatory nucleic acid species. Although mitochondrial toxicity has been a concern, it mainly applies to older NRTIs and is much less pronounced with newer, safer compounds. NRTIs thus represent a compelling case for drug repurposing in the context of age-related diseases. Efforts should be devoted to developing new drugs that overcome NRTIs side effects and retain the anti-inflammaging properties of the parent drugs.