Tier 3 — preclinical

The many faces of SIRT6 in the retina and retinal pigment epithelium

Jie Cheng, Casey J Keuthan, Noriko Esumi

Frontiers in Cell and Developmental Biology 2023 Volume 11, article 1244765

Bibliography

DOI: 10.3389/fcell.2023.1244765
PubMed: PMID 38016059
PubMed Central: PMC10646311
Funding: This work was supported by research grants from the BrightFocus Foundation (M2015220 to NE), the US National Institutes of Health (R01EY016398 to NE, R01EY031714 to JC, and core grant P30EY001765 to the Wilmer Eye Institute), and the Maryland Stem Cell Research Fund (2021-MSCRFF-5596 to CK).
Competing interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Study snapshot

Design	Narrative review of SIRT6 biology across a range of biological contexts, then focused synthesis of SIRT6's specific roles in retinal photoreceptors, retinal ganglion cells, Müller glia and the retinal pigment epithelium.
Model	Not applicable — narrative review of published literature. Reviewed evidence spans Sirt6 knockout mice, RPE-specific Sirt6 deletion, primary retinal ganglion cell culture, ARPE-19 and other RPE cell lines, and one primate (cynomolgus monkey) developmental model.
Sample	Not applicable.
Intervention	Not applicable.
Duration	Not applicable.
Endpoints	Not applicable — review synthesis of published mechanistic, preclinical and cell-based data.

What the study showed, in plain terms

The retina is the light-sensing layer at the back of the eye. Just behind it sits the retinal pigment epithelium (RPE), a single layer of cells that feeds the photoreceptors, recycles used visual pigment, and manages waste. Photoreceptors run almost entirely on glucose; the RPE converts that glucose into lactate and hands it back. Both cell types are unusually vulnerable to oxidative stress because they process light for a living.

This narrative review, written by three vision researchers at the Wilmer Eye Institute at Johns Hopkins, brings together what is currently known about SIRT6 — a longevity enzyme first characterised for its roles in DNA repair, chromatin regulation and metabolism — inside the eye. SIRT6 regulates glucose handling, activates antioxidant defences through the NRF2 pathway, controls autophagy, dampens NF-κB-driven inflammation, and manages stress granules. Each of these matters in the retina and RPE.

The review covers evidence that SIRT6 loss in mice produces retinal dysfunction, that SIRT6 protects retinal ganglion cells from oxidative injury, that SIRT6 regulates the epigenetic state of Müller glia, and that SIRT6 overexpression protects the RPE from oxidative damage. It also flags a complication: because photoreceptors need glycolysis to survive, blunt SIRT6 activation that suppresses glycolysis (as it does in the liver) could be counterproductive in the eye. The authors close with a call for retina-appropriate SIRT6-targeted strategies for blinding diseases including age-related macular degeneration, retinitis pigmentosa and diabetic retinopathy.

Key findings

SIRT6 is highly expressed in ocular tissues. All seven sirtuins are present in the retina, with SIRT1 and SIRT6 particularly enriched.
SIRT6 exerts six major functional axes relevant to the eye: histone deacetylation (H3K9, H3K56, H3K18), DNA repair (via PARP1 mono-ADP-ribosylation and BER/NER), antioxidant defence (NRF2 coactivation and FOXO3 activation of catalase), mitochondrial biogenesis and dynamics, autophagy induction (via AKT–mTOR suppression), and NF-κB repression driving anti-inflammatory M2 macrophage polarisation.
In retinal ganglion cells, SIRT6 activates the NRF2/ARE antioxidant pathway by inhibiting BACH1, protecting against hydrogen-peroxide-induced apoptosis.
In the RPE, SIRT6 overexpression protects against oxidative stress by preserving expression of catalase (via FOXO3), inhibiting NF-κB signalling and suppressing BACH1. SIRT6 also induces autophagy, which is critical for RPE homeostasis and lost in age-related macular degeneration.
SIRT6 is essential for normal retinal function: full-body Sirt6 knockout mice show retinal dysfunction; retina-specific Sirt6 ablation attenuates photoreceptor degeneration in a retinitis pigmentosa model by increasing aerobic glycolysis, illustrating that SIRT6's suppression of glycolysis is context-dependent and can be either protective or harmful depending on cell type.
SIRT6 controls the epigenetic state of Müller glia, affecting their reprogramming capacity — relevant to retinal regeneration strategies.
The review notes SIRT6's newly described role in mitochondrial homeostasis (citing Smirnov et al. 2023) as an emerging axis with likely retinal implications given the retina's exceptional mitochondrial burden.

What this study can and cannot tell us

Narrative review, not a systematic review. No pre-specified inclusion criteria or risk-of-bias assessment. The synthesis reflects author selection.

The eye-specific evidence base is thin: much of the SIRT6 biology reviewed derives from non-ocular tissues (liver, brain, muscle, cardiovascular), extrapolated to the retina and RPE. Direct retinal or RPE work is limited to a handful of primary studies, most in mice or immortalised cell lines. No human clinical evidence for SIRT6 modulation in ocular disease exists.

A therapeutic tension is explicitly acknowledged by the authors: SIRT6's protective roles in the RPE (via NRF2 and autophagy) sit alongside SIRT6's suppression of glycolysis, which is required by photoreceptors. A systemic SIRT6 activator could plausibly harm photoreceptors while protecting the RPE. Retina-appropriate delivery and dosing strategies do not yet exist.

Individual mechanistic claims within the review are supported by single reports in some cases and multiple independent reports in others — readers should not treat all cited mechanisms as equally well-established.