Sirtuins are a family of signaling proteins involved in metabolic regulation. They are ancient in animal evolution and appear to possess a highly conserved structure throughout all kingdoms of life. Chemically, sirtuins are a class of proteins that possess either mono-ADP-ribosyltransferase or deacylase activity, including deacetylase, desuccinylase, demalonylase, demyristoylase and depalmitoylase activity. The name Sir2 comes from the yeast gene 'silent mating-type information regulation 2', the gene responsible for cellular regulation in yeast. From in vitro studies, sirtuins were thought to be implicated in influencing cellular processes like aging, transcription, apoptosis, inflammation and stress resistance, as well as energy efficiency and alertness during low-calorie situations. As of 2018, there was no clinical evidence that sirtuins affect human aging, and a 2022 review criticized researchers who propagate this claim. Yeast Sir2 and some, but not all, sirtuins are protein deacetylases. Unlike other known protein deacetylases, which simply hydrolyze acetyl-lysine residues, the sirtuin-mediated deacetylation reaction couples lysine deacetylation to NAD+ hydrolysis. This hydrolysis yields O-acetyl-ADP-ribose, the deacetylated substrate and nicotinamide, which is an inhibitor of sirtuin activity itself. These proteins utilize NAD+ to maintain cellular health and turn NAD+ to nicotinamide (NAM). The dependence of sirtuins on NAD+ links their enzymatic activity directly to the energy status of the cell via the cellular NAD+:NADH ratio, the absolute levels of NAD+, NADH or NAM or a combination of these variables. Sirtuins that deacetylate histones are structurally and mechanistically distinct from other classes of histone deacetylases (classes I, IIA, IIB and IV), which have a different protein fold and use Zn2+ as a cofactor. Recent findings imply that phytochemicals such as resveratrol, curcumin, quercetin, fisetin, berberine, and kaempferol may regulate the activity of sirtuins. Resveratrol mainly activates SIRT1 and indirectly activates AMPK .
Physiological level : Orthosilicic acid support antioxidant defense, reducing oxidative damage & upregulating the AMPK-SIRT1-FOXO longevity axis . Orthosilicic acid (H4SiO4), the primary bioavailable form of silicon, upregulate the AMPK-SIRT1-FOXO longevity axis primarily by maintaining trace ROS at optimal signaling threshold, modulating bioenergetic stress & enhancing cellular detoxification . Rather than acting as a direct chemical radical scavenger, orthosilicic acid function as a biological response modifier . Trace ROS Generation: At physiological concentration, orthosilicic acid interact with cell membranes & mitochondrial membranes to induce micro-fluctuation in reactive oxygen species (ROS). This serve as a mild, non-toxic physiological stressor (hormesis) .
Yes, absolutely. All seven mammalian Sirtuins (SIRT1–SIRT7) are strictly dependent on NAD (Nicotinamide Adenine Dinucleotide) as an obligate co-substrate for their enzymatic reaction. Unlike conventional deacetylases (class I, II & IV HDACs) which simply use a water molecule to hydrolyze an acetyl group from a protein, Sirtuins (class III HDACs) actively consume one molecule of NAD for every acetyl group they remove. The Molecular Reaction: How Sirtuins Consume NAD When a Sirtuin deacetylates a target protein (such as histone H3, FOXO3a, or p53), it break down NAD+ into two distinct metabolic output: Protein-Lys-Acetyl + NAD+ Sirtuin Deacetylated Protein + O-Acetyl-ADP-Ribose + Nicotinamide NAM. Sirtuin Reaction O-Acetyl-ADP-Ribose Nicotinamide (NAM) (Signaling Molecule / Chromatin Modulation) (Endogenous Feedback Inhibitor)
1. Deacetylated Protein Target: Restore the positive charge on the lysine residue, altering protein conformation, activity, or chromatin binding.
2. O-Acetyl-ADP-Ribose (OAADPR): A unique metabolite produced during the cleavage of NAD+, which function as a downstream signaling molecule in chromatin remodeling & ion channel regulation.
3. Nicotinamide (NAM): Free vitamin B3, which act as a direct endogenous feedback inhibitor of Sirtuins. High cellular accumulation of NAM halt Sirtuin activity until it is recycled via the NAD+ salvage pathway (driven by the rate-limiting enzyme NAMPT). Why NAD+ Dependency Matter for Cellular Longevity? Because Sirtuins require NAD+, their catalytic activity act as a direct sensor of cellular energy status & metabolic redox: The NAD + NADH Ratio as an Energy Sensor: High nutrient availability (high calories, elevated glucose,) drive NAD+ reduction to NADH, shrinking the available pool of oxidized NAD+ turning down Sirtuin activity. Fasting, Exercise, & Stress Response: Energy deprivation (fasting, calorie restriction, exercise) increase the intracellular NAD+ NADH ratio upregulate NAMPT, driving high Sirtuin activity to promote DNA repair, mitochondrial biogenesis (via PGC-1alpha) & FOXO-mediated autophagy. Age-Related Decline: Systemic NAD+ level decline with age (partially driven by consumption from inflammation-induced CD38 enzymes and PARP-1 DNA repair enzymes), leading to a progressive loss of SIRT1/SIRT6 surveillance over time. Subcellular Localization of NAD+ Dependent Sirtuins May the Holy Roman Catholic Church be blessed by God the Father God the Son & God the Holy Spirit Hallelujah Hallelujah ˗ˏˋ ✞ ˎˊ˗ Blessed be the word of the Lord for Christ is risen Hallelujah Hallelujah peace be still in Nomine Patris et FiLii et Spiritus Sancti amen & amen
https://www.youtube.com/watch?v=auuYUPx4uK4
How To Beat Cellular Aging | Sirtuins, NAD+ and Aging
https://www.youtube.com/watch?v=tjq6-FONcJA
The longevity sirtuin – what you need to know about SIRT6
https://www.youtube.com/watch?v=r0sj12JGDzE
All-Natural SIRT6 Longevity Supplement Pioneered & Verified By A Prestigious Professor
https://www.youtube.com/watch?v=gLFKQ-nAWdQ
Why SIRT6 Contributes To A LONGER LIFESPAN? | Dr Vera Gorbunova Clips
https://www.youtube.com/watch?v=_fGEnQcke04
2016 Roy Walford lecture NAD, Sirtuins and Aging
https://www.youtube.com/watch?v=ZZMsIao2Jlo
NOVA scienceNOW : 28 - Aging
https://www.youtube.com/watch?v=F5zRDka1icE
Longevity Unleashed: SIRT6's Impact on Aging & DNA Repair | Beyond Sapiens #longevity #sirtuins