SIRT6 is a multifaceted protein with diverse roles in cellular processes, including aging, metabolism, inflammation, and cardiovascular diseases. As a NAD+-dependent enzyme, it possesses deacetylase, ADP-ribosyltransferase, and long-chain fatty acid deacylase activities, which enable it to regulate various biological functions. In the context of aging, SIRT6 has been recognized for its role in genomic stability, telomere maintenance, and DNA repair, earning it a reputation as a longevity-associated protein. It contributes to the preservation of telomere integrity by deacetylating histone H3 at lysine 9 (H3K9), which helps stabilize the chromatin structure near telomeres. Metabolically, SIRT6 plays a crucial role in glucose and lipid homeostasis. SIRT6 also has a significant impact on inflammation and oxidative stress. It can reduce inflammation by inhibiting the NF-κB pathway and promote antioxidant responses through the NRF2-HO-1 pathway, thereby protecting cells from oxidative damage. Conversely, SIRT6 has also been shown to promote the secretion of pro-inflammatory cytokines like TNF-α, indicating a complex role in inflammatory responses. In cardiovascular health, SIRT6 is protective against diseases such as atherosclerosis, cardiac hypertrophy, and heart failure. It can prevent endothelial dysfunction, reduce vascular inflammation, and promote cardiac cell survival under stress conditions. The protective effects of SIRT6 in the cardiovascular system are attributed to its ability to modulate gene expression and metabolic pathways that are critical for maintaining cardiac function and vascular integrity.