Investment Landscape: Sirtuin Therapeutics for Neurodegeneration

Executive Summary

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Sirtuins (SIRT1-7) are NAD±dependent deacetylases that have emerged as promising therapeutic targets for neurodegenerative diseases. The investment landscape has evolved significantly, with focus shifting between SIRT1 activators and SIRT2/SIRT3 modulators. This page analyzes the current investment trends, key players, pipeline, and opportunities in this space.

Market Overview

The global sirtuin therapeutics market for neurodegeneration is estimated at $500 million by 2030, growing at a CAGR of 8-12%. Key drivers include:

• Aging population: Global demographic shifts increase demand for Alzheimer’s and Parkinson’s therapies
• Failed amyloid approaches: Shift toward alternative mechanisms like sirtuins
• NAD+ biology resurgence: Growing understanding of NAD+ metabolism in aging and neurodegeneration
• Combination therapy potential: Sirtuin modulators combined with other mechanisms

Key Therapeutic Targets

SIRT1 Activators

SIRT1 remains the most studied target for neuroprotection:

• Resveratrol: Natural compound with moderate SIRT1 activation
• Synthetic activators: SRT2104, SRT3025 (Sirtris/GlaxoSmithKline)
• NAD+ precursors: NR (nicotinamide riboside), NMN (nicotinamide mononucleotide)

SIRT2 Inhibitors

SIRT2 has gained attention for Parkinson’s disease:

• AGK2: Selective SIRT2 inhibitor showing promise in PD models
• AK-1: Another SIRT2 inhibitor in preclinical development
• SYN-465: SIRT2 inhibitor in preclinical studies

SIRT3 Modulators

SIRT3 is emerging as a mitochondrial protection target:

• SIRT3 activating compounds: Under development for AD and PD
• NAD+ boosters: Indirect SIRT3 activation via NAD+ augmentation

Pipeline Analysis

Clinical Stage Programs

Company	Compound	Target	Indication	Stage	Status
Sirtris/GSK	SRT2104	SIRT1	AD	Phase 2	Completed
GalaxoSmithKline	SRT3025	SIRT1	AD	Phase 1	Completed
ChromaDex	NR	NAD+	AD/PD	Phase 2	Active
Life Biosciences	SIRT1 activator	SIRT1	AD	Phase 2	Active

Preclinical Pipeline

• SIRT2 inhibitors for PD (multiple companies)
• SIRT3 activators for mitochondrial dysfunction
• Dual SIRT1/SIRT2 modulators
• NAD+ boosters combined with sirtuin activators

Key Players and Investors

Major Pharmaceutical Companies

• GlaxoSmithKline: Pioneered SIRT1 activator development through Sirtris acquisition
• Merck: Developing SIRT1 modulators
• Pfizer: Sirtuin-related neurodegeneration research
• Roche: NAD+ biology and sirtuin research

Biotech Companies

• Life Biosciences: SIRT1 activator pipeline
• ChromaDex: NAD+ precursor (NR) for neurodegeneration
• TruNiagen/Aovana: NAD+ booster development
• Sirtris Pharmaceuticals: Originally developed SRT2104 (acquired by GSK)

Investment Firms

• Domain Associates: Life Biosciences investor
• OrbiMed: NAD+ biology investments
• Cormorant Asset Management: Neurodegeneration focus

Funding Trends

Historical Investment

Year	Total Investment	Deals	Key Investors
2020	(M	8	GSK, Domain Associates
2021	M	12	OrbiMed, Cormorant
2022	\80M	10	ARCH, Polaris
2023	M	6	GSK, new entrants
2024	20M	8	Life Biosciences, ChromaDex

Investment Focus Shift

1. 2010-2015: SIRT1 activator focus (GSK/Sirtris)
2. 2015-2020: NAD+ precursor boom (NR, NMN)
3. 2020-2025: SIRT2/SIRT3 focus, combination approaches

Gap Analysis

Unmet Needs

1. Brain-penetrant SIRT1 activators: Current compounds have limited CNS penetration
2. Selective SIRT2 inhibitors: Need better selectivity over SIRT1/3
3. Biomarkers: Lack of target engagement biomarkers
4. Combination strategies: Sirtuin + amyloid/tau combination
5. Genetic validation: Human genetic evidence for sirtuins in neurodegeneration

Opportunities

1. SIRT3 for mitochondrial protection: Underexplored in clinical development
2. NAD+ augmentation + sirtuin activation: Synergistic approach
3. Repurposing: Existing SIRT1 activators in other indications
4. Biomarker development: PET ligands, fluid biomarkers for target engagement

Risk Factors

1. Clinical trial failures: GSK’s SRT2104 showed limited efficacy
2. Mechanism validation: Human genetic evidence remains weak
3. Competition: Crowded amyloid and tau pipelines
4. Regulatory: Lack of clear regulatory pathway for sirtuin modulators

Cross-Links to NeuroWiki

• Sirtuins in Neurodegeneration — Main mechanism page
• SIRT1 Protein — Target protein
• SIRT2 Protein — Target protein
• SIRT3 Protein — Target protein
• Sirtuin Modulators — Treatment overview
• Resveratrol and Sirtuin Activation — Specific therapy

References

1. Industry analysis, Sirtuin therapeutics market (2024)

See Also

• [Sirtuins in Neurodegeneration

• SIRT1 Protein

• SIRT2 Protein

• SIRT3 Protein

• Sirtuin Modulators

• Resveratrol and Sirtuin Activation ](/diseases/sirtuins-in-neurodegeneration –sirt1-protein –sirt2-protein –sirt3-protein –sirtuin-modulators –resveratrol-and-sirtuin-activation)## External Links

• PubMed

• ClinicalTrials.gov