Conservation of physiological dysregulation signatures of aging across primates

Abstract

Two major goals in the current biology of aging are to identify general mechanisms underlying the aging process and to explain species differences in aging. Recent research in humans suggests that one important driver of aging is dysregulation, the progressive loss of homeostasis in complex biological networks. Yet, there is a lack of comparative data for this hypothesis, and we do not know whether dysregulation is widely associated with aging or how well signals of homeostasis are conserved. To address this knowledge gap, we use unusually detailed longitudinal biomarker data from 10 species of nonhuman primates housed in research centers and data from two human populations to test the hypotheses that (a) greater dysregulation is associated with aging across primates and (b) physiological states characterizing homeostasis are conserved across primates to degrees associated with phylogenetic proximity. To evaluate dysregulation, we employed a multivariate distance measure, calculated from sets of biomarkers, that is associated with aging and mortality in human populations. Dysregulation scores positively correlated with age and risk of mortality in most nonhuman primates studied, and signals of homeostatic state were significantly conserved across species, declining with phylogenetic distance. Our study provides the first broad demonstration of physiological dysregulation associated with aging and mortality risk in multiple nonhuman primates. Our results also imply that emergent signals of homeostasis are evolutionarily conserved, although with notable variation among species, and suggest promising directions for future comparative studies on dysregulation and the aging process.

Keywords: Mahalanobis distance; aging; biomarkers; dysregulation; homeostasis; nonhuman primates.

Figure 1

Estimated effects of age on D_M, shown separately by species and sex. D_M and age were centered to 0 and scaled to 1 standard deviation. Thus, the coefficient reflects the estimated effect at the mean age, and effect sizes can be compared across species. Error bars represent 95% confidence intervals. Note that this is a graphical representation of separate effects by sex, but significance of effects is interpreted from full model results (see Table S3)

Figure 2

Correlation between D_M scores calculated using each species as a reference for itself and D_M scores calculated using combined‐species data as a reference population: Set 1 using variable numbers of biomarkers for 11 species and Set 2 using the same 12 biomarkers for 10 species. D_M was centered to 0 and scaled to 1 standard deviation to facilitate comparison among species. r = Pearson's correlation coefficients between the two D_M scores for each species (all p < 0.001)

Figure 3

Correlation matrices for correlations (r) between D_M scores calculated using each species as a reference for itself and using each species as the reference for the others: Set 1 using variable numbers of biomarkers for 11 species and Set 2 using the same 12 biomarkers for 10 species. Rows are species for which D_M is calculated; columns are species used as the reference. The combined‐species population is presented in the last column and row for visual reference but was not used in calculating r between phylogeny and D_M. Each cell visually represents r between D_M scores for the row species calculated using itself or the column species as the reference. Positive r values are in blue and tilt to the right; negative values are in red and tilt to the left. Color intensity and ellipse eccentricity scale to the strength of r, that is, weak correlations appear as faint boxes, and strong correlations appear as dark, thin ellipses. Matrix diagonals represent perfect correlation (r = 1), except for the bottom‐right cell, where the combined reference (last column) was a random subsample of the combined population (last row). Species are ordered by phylogenetic proximity to humans. Black interior lines indicate divisions between general species groupings from Table 1