The Science of Aging
Everyone should die young, as late in life as possible
Geroscience holds that aging itself is the primary risk factor for most chronic diseases. By therapeutically modifying the biology of aging, we can prevent or delay multiple conditions simultaneously — rather than treating them one by one after they appear.
New Publication
Featured Research
GeroScience — 2026
The TyrRS Cascade: Circadian Gating of Neuronal DNA Repair and Its Collapse in Aging
About this paper
This paper describes how Tyrosyl-tRNA synthetase (TyrRS/YARS1) operates on a circadian cycle to gate three neuroprotective pathways — PARP1-mediated DNA repair, TRIM28/NuRD translational regulation, and LIN9/DREAM complex derepression — collectively termed the TyrRS Cascade. In aging and Alzheimer's disease, elevated tyrosine levels flatten TyrRS's circadian rhythm, leading to impaired oxidative DNA damage repair and accelerated neurodegeneration.
DOI: 10.1007/s11357-026-02532-0 ↗Key findings
Conference Presentation
AAIC 2026 — London
FLL-001, a First-in-class YARS1 (TyrRS) Modulator in Preclinical Development for Alzheimer's Disease
Mathew S, Seiden D, Smith WK — Functional Longevity Labs, Inc.
FLL-001 is a first-in-class YARS1 modulator with picomolar neuroprotective potency, validated on-target mechanism, clean genotoxicity and cardiac safety profiles, and favorable oral pharmacokinetics in mice. These findings support advancement of FLL-001 toward IND-enabling studies as a novel multi-target therapeutic for Alzheimer's disease.
Origin & Mission
The National Geroscience Initiative
In May 2021, a consensus symposium organized by the National Institute on Aging, the Uniformed Services University of the Health Sciences, and the University of South Carolina launched a national conversation on geroscience — producing a White Paper and Virtual Symposium that defined a national research vision for the field.
White Paper
White Paper on a National Investment in Geroscience
Defining a National Research Vision Utilizing the Biology of Aging to Optimize Human Performance, Healthspan and Lifespan
Prepared for the Consensus Symposium — May 7, 2021 — NIA, USUHS, University of South Carolina
Journal Publication
Symposium Proceedings — Special Edition
The proceedings of the 2021 Consensus Symposium were published as a special edition of GeroScience, the official journal of the American Aging Association.
DOI: 10.1007/s11357-021-00371-9 ↗Video Proceedings
2022 Geroscience Symposium
Video proceedings from the 2022 Geroscience Symposium, including presentations on the science of aging, healthspan, and geroscience therapeutics.
Watch on YouTube ↗2019 Symposium — Published Articles
State of the Science Symposium: Metabolic Pathways and Therapeutics to Promote Resilience, Rehabilitation and Delayed Aging
October 25, 2019 — Uniformed Services University of the Health Sciences, Bethesda, MD — Co-Chaired by Donald K. Ingram, PhD and William K. Smith, MD
Intermittent fasting: from calories to time restriction
Duregon E, Pomatto-Watson LCD, Price NL, Bernier M, de Cabo R. GeroScience (2021)
DOI: 10.1007/s11357-021-00335-z ↗Glycolytic Inhibition: Effective Strategy for Developing Calorie Restriction Mimetics
Ingram DK, Roth GS. GeroScience (2021)
DOI: 10.1007/s11357-020-00298-7 ↗Diabetes Medications as Potential Calorie Restriction Mimetics: A Focus on the Alpha-Glucosidase Inhibitor Acarbose
Smith DL Jr, Orlandella RM, Allison DB, Norian LA. GeroScience (2021)
DOI: 10.1007/s11357-020-00278-x ↗Geroscience Perspective on Immune Resilience and Infectious Diseases: A Case For Metformin
Justice JN, Gubbi S, Kulkarni AS, Bartley JM, Kuchel GA, Barzilai N. GeroScience (2021)
PubMed: 32902818 ↗Longevity Pathways in Stress Resistance: Targeting NAD and Sirtuins to Treat the Pathophysiology of Hemorrhagic Shock
Baur J, Sims C, Labiner H, Shah S. GeroScience (2021)
DOI: 10.1007/s11357-020-00311-z ↗Effect of Rapamycin on Aging and Age-Related Diseases: Past and Future
Selvarani R, Mohammed Jazir S, Richardson A. GeroScience (2021)
DOI: 10.1007/s11357-020-00274-1 ↗Towards Resolving the Enigma of the Dichotomy of Resveratrol: Cis- and Trans-Resveratrol Have Opposite Effects on TyrRS-Regulated Parp1 Activation
Jhanji M, Rao CN, Mathew S. GeroScience (2021) — Foundational to FLL’s therapeutic approach
DOI: 10.1007/s11357-020-00295-w ↗Mitochondrial-Derived Peptides in Aging and Age-Related Diseases
Kim S-J, Miller B, Kumagai H, Silverstein AR, Flores M, Yen K. GeroScience (2021)
DOI: 10.1007/s11357-020-00262-5 ↗From Bedside to Battlefield: Intersection of Ketone Body Mechanisms in Geroscience with Military Resilience
Stubbs BJ, Koutnik AP, Volek JS, Newman JC. GeroScience (2021)
DOI: 10.1007/s11357-020-00277-y ↗The concept of the Health Gap — the period between the end of healthspan and the end of lifespan — was formally introduced in this White Paper by Dr. William K. Smith, who continues to advance geroscience through Functional Longevity Labs and its Cooperative Research and Development Agreement with the NIA.
Geroscience Primer
Core Concepts
The foundational ideas behind geroscience — and how FLL's research connects to them.
The Health Gap
The period between the end of healthspan and the end of lifespan — a concept coined by FLL founder Dr. William K. Smith in 2019. Geroscience aims to narrow this gap by targeting the aging process itself.
Circadian Gating
Many cellular repair programs operate on a daily (circadian) schedule. TyrRS has a circadian cycle that gates DNA repair activity. When aging flattens this rhythm, neuronal repair fails — a key mechanism in AD.
The TyrRS Cascade
Three neuroprotective pathways governed by Tyrosyl-tRNA synthetase: PARP1-mediated DNA repair, TRIM28/NuRD translational regulation, and LIN9/DREAM complex derepression. Collapse of this cascade drives AD pathology.
Tyrosine & Aging
Elevated circulating tyrosine in aging and Alzheimer's disease depletes neuronal TyrRS, inducing oxidative DNA damage and inhibiting protein synthesis. Dietary tyrosine management may be a modifiable risk factor.
Geroscience Hypothesis
Therapeutically addressing the biology of aging can directly prevent or delay multiple chronic diseases simultaneously — rather than treating individual disease manifestations after they appear. FLL's pipeline is built on this principle.
AMP-AD & NIA Partnership
TyrRS/YARS1 was nominated as a therapeutic target by the NIH Accelerating Medicines Partnership® for Alzheimer's Disease. FLL operates under a CRADA with the National Institute on Aging at NIH.
Literature
Key Publications
Peer-reviewed research underpinning the TyrRS Cascade and FLL's therapeutic programs.
The TyrRS Cascade: Circadian Gating of Neuronal DNA Repair and Its Collapse in Aging
DOI: 10.1007/s11357-026-02532-0 ↗Cis- and trans-resveratrol have opposite effects on histone serine-ADP-ribosylation and tyrosine-induced neurodegeneration
DOI: 10.1038/s41467-022-30785-8 ↗LIN9/DREAM complex derepression and TyrRS-dependent neuroprotective signaling
A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol
DOI: 10.1038/nature14028 ↗Translating this science into therapeutics
FLL-001 is a first-in-class YARS1 Chronomodulator currently in Pre-IND development for Alzheimer's disease.