Biology of Healthy Aging: Biological Hallmarks of Stress Resistance Related and Unrelated to Longevity in Humans

Abstract

Stress resistance is highly associated with longer and healthier lifespans in various model organisms, including nematodes, fruit flies, and mice. However, we lack a complete understanding of stress resistance in humans; therefore, we investigated how stress resistance and longevity are interlinked in humans. Using more than 180 databases, we identified 541 human genes associated with stress resistance. The curated gene set is highly enriched with genes involved in the cellular response to stress. The Reactome analysis identified 398 biological pathways, narrowed down to 172 pathways using a medium threshold (p-value < 1 × 10^-4). We further summarized these pathways into 14 pathway categories, e.g., cellular response to stimuli/stress, DNA repair, gene expression, and immune system. There were overlapping categories between stress resistance and longevity, including gene expression, signal transduction, immune system, and cellular responses to stimuli/stress. The categories include the PIP3-AKT-FOXO and mTOR pathways, known to specify lifespans in the model systems. They also include the accelerated aging syndrome genes (WRN and HGPS/LMNA), while the genes were also involved in non-overlapped categories. Notably, nuclear pore proteins are enriched among the stress-resistance pathways and overlap with diverse metabolic pathways. This study fills the knowledge gap in humans, suggesting that stress resistance is closely linked to longevity pathways but not entirely identical. While most longevity categories intersect with stress-resistance categories, some do not, particularly those related to cell proliferation and beta-cell development. We also note inconsistencies in pathway terminologies with aging hallmarks reported previously, and propose them to be more unified and integral.

Keywords: aging; endocrine; insulin; longevity; metabolism; nuclear integrity; progeria; stress damage; stress resilience; stress resistance.

Figure 1

The 14 general pathways linked to the stress-resistance genes (Table S1). They are color-coded to the number of occurrences of the pathway. Green represents the general pathway with the most hits and red represents the general pathway with the least hits. To the right of the general pathways are the specific pathways. The specific pathways are color-coded to the number of occurrences of the pathway in relation to the other most frequent specific pathways.

Figure 2

Seven general pathways associated with the longevity genes (Table S2). The color of the general pathway represents the number of occurrences of the pathway relative to the other general pathways. The pathways in green have the greatest number of hits, whereas the red have the fewest number of hits. To the right of the general pathways are the most frequent specific pathways. The specific pathways are color-coded in relation to the other most frequent specific pathways, with green being the most frequent and red being the least frequent.

Figure 3

Compares and contrasts the general pathways linked to the stress-resistance genes and longevity genes. Eight general pathways are linked to only stress resistance, whereas one general pathway is linked to only longevity. Six general pathways are linked to both stress resistance and longevity.

Figure 4

Interaction network diagrams of overlapped pathways. (A) Overall network of stress-resistance genes, (B) cellular response to stimuli (stress), (C) gene expression, (D) signal transduction, (E) autophagy, (F) immune system, (G) metabolism (carbohydrate). Red arrows indicate a cluster of the nuclear transport and integrity genes (NUPs), although the genes are embedded throughout the pathways, as described in the text. To generate these diagrams, we used the pathways with the highest number of hits in each category (Table S1).