The good and the bad of being connected: the integrons of aging

Abstract

Over 40 years ago, Francois Jacob proposed that levels of 'integrons' explain how biological systems are constructed. Today, these networks of interactions between tissues, cells, organelles, metabolic pathways, genes, and individual molecules provide key insights into biology. We suggest that the wiring and interdependency between subsystems within a network are useful to understand the aging process. The breakdown of one subsystem (e.g. an organelle) can have ramifications for other interconnected subsystems, leading to the sequential collapse of subsystem functions. But yet, the interconnected nature of homeostatic wiring can provide organisms with the means of compensating for the decline of one subsystem. This occurs at multiple levels in an organism-for example, between organelles or between tissues. We review recent data that highlight the importance of such interconnectivity/communication in the aging process, in both progressive decline and longevity assurance.

Figure 1. A cascade of interactions between organelles help define the aging process

The myriad of connections between subsystems (colored spheres) in a cell are represented here as gray arrows. The vacuole (V), mitochondria (M) and nucleus (N) are represented in this network schematic. As described in the text, reduced vacuole function (indicated by a perforated circle – bottom left) early in a yeast cell’s life span, leads to an apparent pathological interaction (red arrow) with mitochondria that in turn leads to reduced mitochondrial function (bottom right). The dysfunctional mitochondria no longer produce sufficient iron-sulfur clusters (loss of green arrow), which are required for normal DNA replication & repair in the nucleus.

Figure 2. Communication of proteostasis stress networks between cells and tissues is essential for metazoan aging

Signaling between cells is part of the aging process. In C. elegans, mitochondrial proteotoxic stress in the nervous system leads to mitokines being sent to other cells. This signaling elicits a mitochondrial stress response in distal cells of this metazoan and essential for the increased longevity of animals with mitochondrial proteome imbalance. Similarly, this phenomenon has been observed for the IRE-1/XBP-1 endoplasmic reticulum stress response as well as the heat shock response, both of which can extend lifespan when ectopically induced.