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Biology subjects

Pridham, G.

Publications and source records attributed to Pridham, G..

3 recordsLinked to original sources

Dynamics of the end-of-life phase explained by the saturating removal model

End of life is characterized by a phase of rapid physiological decline and high morbidity, phenotypically observed as the "Smurf" phase in Drosophila, metabolic end-of-life dysregulation in mice, and end-stage frailty in humans. Existing two-phase aging models often conceptualize this end-of-life phase as a discrete biological state. Here, we demonstrate that a continuous stochastic model of damage accumulation, the saturating removal (SR) model, captures these multi-species morbidity dynamics. By defining the end-of-life phase as a stochastic crossing of a sub-lethal damage threshold, the SR model accurately reproduces empirical end-of-life dynamics across flies, mice, and humans. The model predicts a surprising temporary reduction in hazard shortly after entering the end-of-life phase consistent with empirical data in all three organisms. It also correctly predicts a shortening twilight phenomenon where the mean duration of the end-of-life phase decreases the later its onset. We conclude that end-of-life dynamics are consistent with universal features of a driver of aging crossing a threshold for end-of-life morbidity and then a threshold for death.

systems biology↗

Heritability of human lifespan is about 50% when confounding factors are addressed

The heritability of human lifespan is a fundamental question in biology. Current estimates of heritability are low - twin studies show that about 20-25% of the variation in lifespan is explained by genetics, and some large family pedigree studies suggest it is as low as 7%. However, these studies do not distinguish between deaths driven by intrinsic biological processes and deaths caused by extrinsic factors such as accidents or infections. Here we use mathematical modeling and analyses of twin cohorts raised together and apart to show that extrinsic mortality skews heritability estimates by driving down measured lifespan correlations among twin pairs. We also identify a nonlinear effect of the cutoff age--the minimum age of death included in each study -- on estimates of heritability. Correcting for these factors more than doubles previous estimates, revealing that intrinsic heritability of human lifespan is above 50%. Such high heritability is similar to most other complex human traits. We thus challenge the consensus that genetics has only a minor effect on lifespan and show that genes explain the majority of lifespan variation. Since genes are important, understanding the genetics of longevity can reveal aging mechanisms and inform medicine and public health.

genetics↗

Pregnancy laboratory test dynamics resemble rejuvenation of some organs and aging of others

Aging and pregnancy both involve changes in many physiological systems. Some of these changes are similar, leading to suggestions that pregnancy may be a model for aging. Recent studies using DNA methylation clocks showed apparent aging during gestation which resolves postpartum. Since aging and pregnancy are complex, it is important to compare them in terms of many physiological parameters and at many time points. Here, we analyzed cross-sectional data on 62 lab tests at weekly resolution in 300,000 pregnancies and 1.4 million nonpregnant females aged 20-80. We trained a regression model to predict age from lab tests. Apparent age dropped by 8 years in early pregnancy, rose by 30 years towards delivery, and recovered postpartum. Certain systems exhibited rejuvenation, with opposite trends in pregnancy and aging, including renal, iron, and most liver tests. Others, such as coagulation, thyroid, muscle, and metabolic systems, showed apparent aging. Some systems displayed mixed trends. Notably, in the systems that showed apparent aging, the physiological mechanisms for the changes differed between pregnancy and aging. Pregnancy complications led to an additional apparent aging of 4-8 years. We conclude that pregnancy has features of rejuvenation for some systems, but its aging-like features involve different mechanisms than true aging. Gestational rejuvenation-like mechanisms may offer clues for slowing aspects of biological aging.

bioinformatics↗