USING CAUSAL AGING BIOMARKERS AND PROTEIN DESIGN TO DEVELOP NOVEL ANTI-AGING INTERVENTIONS - PROJECT SUMMAR…

Assistance award details

Assistance award identifier

ASST_NON_K00AG088431_075

FAIN

K00AG088431

Recipient

THE LELAND STANFORD JUNIOR UNIVERSITY

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.866

Total obligated

$175,965

Period

Sep 3, 2024 – Aug 31, 2029

Fiscal year

2025

Place of performance state

CA

Source file

FY2025_All_Assistance_Full_20261006.zip

Description

USING CAUSAL AGING BIOMARKERS AND PROTEIN DESIGN TO DEVELOP NOVEL ANTI-AGING INTERVENTIONS - PROJECT SUMMARY IN MAMMALS, 5-METHYLCYTOSINE IS THE MOST COMMON FORM OF DNA METHYLATION, AND THE LEVEL OF METHYLATION OF SOME SPECIFIC CPG SITES SHOWS A STRONG CORRELATION WITH AGE. THESE CORRELATIONS CAN BE USED TO BUILD MACHINE LEARNING-BASED MODELS THAT CAN ACCURATELY PREDICT THE AGE OF BIOLOGICAL SAMPLES. BECAUSE THESE MODELS CAN QUANTIFY AGE WITH VERY HIGH ACCURACY, RESEARCHERS HAVE TERMED THEM EPIGENETIC AGING CLOCKS (E.G., HORVATH’S PAN-TISSUE EPIGENETIC CLOCK AND HANNUM’S BLOOD-BASED EPIGENETIC CLOCK). HOWEVER, THE RELIABILITY OF EXISTING EPIGENETIC CLOCKS IS LIMITED, AS THEY ARE BUILT BASED ON PURE CORRELATIONS, AND IT IS UNCLEAR WHETHER AGE- ASSOCIATED METHYLATION CHANGES ARE CAUSAL TO AGING-RELATED PHENOTYPES. A NEW GENERATION OF EPIGENETIC CLOCKS BUILT ON CAUSAL INFORMATION WILL BE MORE RELIABLE AND CAN ENABLE THE POSSIBILITY OF LARGE-SCALE SCREENING OF ANTI-AGING INTERVENTIONS. FOR THE F99 PHASE OF THIS PROPOSAL, I PERFORMED EPIGENOME-WIDE MENDELIAN RANDOMIZATION TO IDENTIFY CPGS POTENTIALLY CAUSAL TO AGING-RELATED TRAITS. THIS CAUSAL INFORMATION WAS THEN INCORPORATED INTO EPIGENETIC CLOCK MODELS TO BUILD CAUSALITY-INFORMED AGING CLOCKS, WHICH ARE SHOWN TO SEPARATE AGE-RELATED DAMAGE FROM ADAPTATION, NAMELY DAMAGE AND ADAPTAGE. I ALSO BUILT CLOCKBASE, A DATABASE THAT CONTAINS OVER 300,000 EXPERIMENTAL SAMPLES FROM GEO WITH THE EPIGENETIC AGE PRE-CALCULATED. I PLAN TO FURTHER STANDARDIZE THE SAMPLE INFORMATION USING LARGE LANGUAGE MODELS AND APPLY THE CAUSALITY-INFORMED BIOMARKERS TO SCREEN FOR ANTI-AGING INTERVENTIONS. IN THE K00 PHASE, I WILL USE THE PROTEIN LANGUAGE MODEL AND PROTEIN DESIGN TOOL TO EXPAND THE UNIVERSE OF ANTI- AGING INTERVENTIONS. SPECIFICALLY, I WILL STUDY THE PROTEIN STRUCTURAL FEATURES ACROSS MAMMALIAN SPECIES WITH VARIOUS LIFESPANS TO UNDERSTAND WHICH FEATURES ARE ASSOCIATED WITH LONGEVITY. THEN, I CAN INCORPORATE THIS INFORMATION INTO