Biology subjects

Perls, T.

Publications and source records attributed to Perls, T..

4 recordsLinked to original sources

bioRxiv2025

METABOLOMIC SIGNATURES OF EXTREME OLD AGE: FINDINGS FROM THE NEW ENGLAND CENTENARIAN STUDY

The New England Centenarian Study (NECS) provides a unique resource for the study of extreme human longevity (EL). To gain insight into biological pathways related to EL, chronological age and survival, we used an untargeted serum metabolomic approach (> 1,400 metabolites) in 213 NECS participants, followed by integration of our findings with metabolomic data from four additional studies. Compared to their offspring and matched controls, EL individuals exhibited a distinct metabolic profile characterized by higher levels of primary and secondary bile acids - most notably chenodeoxycholic acid (CDCA) and lithocholic acid (LCA) - higher levels of biliverdin and bilirubin, and stable levels of selected steroids. Notably, elevated levels of both bile acids and steroids were associated with lower mortality. Several metabolites associated with age and survival were inversely associated with metabolite ratios related to NAD+ production and/or levels (tryptophan/kynurenine, cortisone/cortisol), gut bacterial metabolism (ergothioneine/ trimethylamine N-oxide, aspartate/quinolinate), and oxidative stress (methionine/methionine sulfoxide), implicating these pathways in aging and/or longevity. We further developed a metabolomic clock predictive of biological age, with age deviations significantly associated with mortality risk. Key metabolites predictive of biological aging, such as taurine and citrate, were not captured by traditional age analyses, pointing to their potential role as biomarkers for healthy aging. These results highlight metabolic pathways that may be targeted to promote metabolic resilience and healthy aging.

systems biology↗

bioRxiv2025

Increased Genetic Protection Against Alzheimer's Disease in Centenarians

We constructed a polygenic protective score specific to Alzheimers disease (AD PPS) based on the current literature among the participants enrolled in five studies of healthy aging and extreme longevity in the US, Europe, and Asia. This AD PPS did not include variants on Apolipoprotein E (APOE) gene. Comparisons of AD PPS in different data sets of healthy agers and centenarians showed that centenarians have stronger genetic protection against AD compared to individuals without familial longevity. The current study also shows evidence that this genetic protection increases with increasingly older ages in centenarians (centenarians who died before reaching age 105 years, semi-supercentenarians who reached age 105 to 109 years, and supercentenarians who reached age 110 years and older). However, the genetic protection was of modest size: the average increase in AD PPS was approximately one additional protective allele per 5 years of gained lifetime. Additionally, we show that the higher AD PPS was associated with better cognitive function and decreased mortality. Taken together, this analysis suggests that individuals who achieve the most extreme ages, on average, have the greatest protection against AD. This finding is robust to different genetic backgrounds with important implications for universal applicability of therapeutics that target this AD PPS.

genetics↗

bioRxiv2025

Robust Serum Proteomic Signatures of APOE2

We previously identified a signature of 16 serum proteins that highlighted a role of the e2 allele of APOE in lipid regulation via apolipoprotein B (APOB) and apolipoprotein E (APOE), and in inflammation. The serum proteins were profiled using the aptamer-based Somalogic technology. Here, we validate and expand the serum protein signature of APOE using a combination of mass-spectrometry, ELISA, Luminex, antibody-based Olink proteomics, and blood transcriptomics. We replicate the association between APOB and the e2 allele of APOE, we correct the pattern of association between APOE genotypes and serum level of APOE, and we detect new associations between APOE genotypes and the complex of apolipoproteins APOC1, APOC4, APOC2, APOC3, APOE, APOF and APOL1. In addition, we discover 13 new proteins that correlate with APOE genotypes. This extended signature includes granule proteins CAMP, CTSG, DEFA3, and MPO secreted from neutrophils and points to olfactomedin 4 (OLFM4) as a new target for the prevention of Alzheimers disease.

genetics↗

bioRxiv2022

Rare Genetic Variants Correlate with Better Processing Speed

We conducted a genome-wide association study (GWAS) of Digit Symbol Substitution Test (DSST) scores administered in 4207 family members of the Long Life Family Study (LLFS). Genotype data were imputed to the HRC panel of 64,940 haplotypes resulting in ~15M genetic variants with quality score > 0.7. The results were replicated using genetic data imputed to the 1000 Genomes phase 3 reference panel from two Danish twin cohorts: the study of Middle Aged Danish Twins and the Longitudinal Study of Aging Danish Twins. The GWAS in LLFS discovered 20 rare genetic variants (minor allele frequency (MAF) < 1.0%) that reached genome-wide significance (p-value < 5x10-8). Among these, 18 variants had large protective effects on the processing speed, including rs7623455, rs9821776, rs9821587, rs78704059 on chromosome 3, which were replicated in the combined Danish twin cohort. These SNPs are located in/near two genes, THRB and RARB, that belonged to thyroid hormone receptors family that may influence speed of metabolism and cognitive aging. The gene-level tests in LLFS confirmed that these two genes are associated with processing speed.

genetics↗