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

Highlights

• Interconnectivity and homeostatic feedback are fundamental properties of biological systems.

• Specific nodes in the interconnected network of an organism are more sensitive to change and thus mediate aging.

• Interdependency between subsystems can lead to progressive decline by sequential collapse of homeostasis.

• Cell communication between subsystems can compensate for age-associated decline and may extend life span.

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.

Introduction

Aging is one of the highest risk factors known for most human diseases, including cancer, neurodegeneration, diabetes, and metabolic syndrome. Given the importance of these diseases in the population, as well as other age-associated phenotypes that contribute to frailty as people age, there is a keen interest to define and understand the aging process. In recent decades there have been regular intervals of excitement that ‘the key’ to unlocking our understanding of aging has been discovered. However the number of keys has been increasing with the time spent looking for them and rather than coming to a clearer understanding (unifying theory), the number of hypotheses to define the aging process and explain it has been increasing. While this may be perceived as confusing, more realistically it reflects that as a field, the study of aging is still early in its development. It is at a stage where the process of aging continues to be defined and discoveries continue to help us realize there is still more underlying biology to understand. As a consequence, what we learn from model systems is very important for helping us to define and understand the aging process.

We begin by considering recent developments in the aging field in light of a fundamental property of biological systems — interconnectivity [1]. All levels of interaction contribute to the ultimate phenotype of an organism: interactions between tissues, between cells, between organelles, between metabolic pathways, between genes, between individual molecules and hormones [e.g. [2]]. With the help of network analysis, the complexity of such interactions can be visualized — though admittedly, not always in a manner of easy comprehension — to develop new ideas and questions relevant to the aging process. If we consider organelles as one type of subsystem within a network, then when organelle A declines with age, a connection with organelle B may result in B's decline as well (depicted in Figure 1). These age-relevant connections can come in two flavors. In one case, a normal functional connection may become broken as organelle A declines — for example, A normally provides a biosynthetic product to B. Alternatively, a novel connection is created, with pathological consequences for B, as A declines. It is also possible that more than one subsystem may be sensitive to aging, albeit through distinct routes. How and whether these types of events occur are critical to developing a better understanding about aging.

A second type of interaction important in the aging process is the response of a biological system to changes — that is, the basis of homeostasis and biological anticipation. As an organism ages, what types of response or compensation occur, and what is the consequence of the response? For instance, is compensation ‘successful’ and does it help to prevent dysfunction, or does compensation result in unintended (negative) consequences, throwing different, interconnected, subsystems into dysfunction?

Recent results illustrating the importance of such interconnectivity in the aging process are highlighted below.