Tier 3 — preclinical

Sirtuins in Medicine: Multifaceted Roles in Physiological Processes and Cardiovascular Diseases

Jan Krekora, Oliwia Matuszewska-Brycht, Jerzy Krzysztof Wranicz, Michał Krejca, Krzysztof Kaczmarek, Piotr Merks, Jarosław Drożdż

Biomolecules 2026 Volume 16, issue 6, article 793

Bibliography

DOI: 10.3390/biom16060793
PubMed: PMID 42352261
PubMed Central: PMC13297320
Funding: This research received no external funding.
Competing interests: The authors declare no conflicts of interest.

Study snapshot

Design	Narrative review of the seven mammalian sirtuins (SIRT1–SIRT7), their subcellular localisation, enzymatic activities, roles in ageing and cellular homeostasis, and their involvement in cardiovascular diseases including metabolic cardiomyopathy, myocardial ischaemia–reperfusion injury, cardiac hypertrophy, fibrosis, heart failure, atherosclerosis, coronary artery disease and hypertension.
Model	Not applicable — narrative review of published literature.
Sample	Not applicable.
Intervention	Not applicable.
Duration	Not applicable.
Endpoints	Not applicable — review synthesis of published mechanistic, preclinical and translational data.

What the study showed, in plain terms

Sirtuins are a family of seven enzymes (SIRT1 to SIRT7) that depend on NAD⁺ to do their job. They sit in different parts of the cell — some in the nucleus, some in the mitochondria, one in the cytoplasm — and they help maintain genomic stability, control inflammation, tune metabolism and manage oxidative stress. When their activity drops, the cell struggles with the same problems that define ageing.

This narrative review, written by cardiologists at the Medical University of Lodz and Warsaw, walks through what each sirtuin does in normal physiology and then how each contributes to major cardiovascular diseases — coronary artery disease, heart failure, cardiac hypertrophy, atherosclerosis, myocardial ischaemia–reperfusion injury and hypertension. The authors put particular emphasis on SIRT1, SIRT3 and SIRT6 as the sirtuins with the strongest cardiovascular case: endothelial protection, mitochondrial quality control, redox balance and reduced inflammatory signalling.

The review closes with the current translational landscape: NAD⁺-boosting molecules, small-molecule sirtuin activators (including SRT2104 clinical trial data), and the outstanding challenges — isoform selectivity, tissue targeting and durable clinical evidence — that stand between the mechanistic case and a licensed sirtuin-based therapy.

Key findings

Seven mammalian sirtuins share NAD⁺ dependence but differ in localisation and substrate: SIRT1 (nucleus/cytoplasm), SIRT2 (cytoplasm), SIRT3/4/5 (mitochondria), SIRT6/7 (nucleus). This determines which cardiovascular processes each isoform can influence.
SIRT1, SIRT3 and SIRT6 emerge as the isoforms with the most consistent cardioprotective evidence — endothelial integrity, mitochondrial quality control, oxidative stress buffering, inflammation suppression and myocardial remodelling.
SIRT6 specifically supports smooth muscle cell health, endothelial function, and lipid handling (via PCSK9 and SREBP1/2 regulation), and constrains atherosclerotic plaque development.
Sirtuin dysregulation is documented in metabolic cardiomyopathy, ischaemia–reperfusion injury, cardiac hypertrophy, fibrosis, heart failure (both HFrEF and HFpEF), atherosclerosis, coronary artery disease and hypertension.
Therapeutic strategies reviewed: NAD⁺ precursors (nicotinamide riboside, nicotinamide mononucleotide, nicotinamide) with early human safety data; small-molecule sirtuin activators including SRT2104 (SIRT1 activator, phase II data in type 2 diabetes and healthy smokers); resveratrol and its metabolites; natural compounds targeting SIRT1 and SIRT3.
Isoform selectivity is the dominant unresolved challenge — most existing activators are not truly SIRT-specific, and some sirtuins have context-dependent or opposing effects.

What this study can and cannot tell us

This is a narrative review, not a systematic review or meta-analysis. The authors did not pre-specify inclusion criteria, search strategy or risk-of-bias framework, so the evidence synthesis reflects author selection.

The clinical case rests heavily on preclinical mechanistic and animal-model data. Human intervention data specific to sirtuin activation in cardiovascular disease remains limited — the referenced SRT2104 trials involved healthy smokers and type 2 diabetes surrogate endpoints, not hard cardiovascular outcomes. NAD⁺-precursor trials to date are dose-finding and safety-focused rather than powered on mortality or major adverse cardiac events.

The review does not standardise evidence tiers across the discussed sirtuins — some claims are supported by multiple independent models, others by single reports. Readers should not treat every mechanism described as equally well-established.

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