Life is a Maintenance Problem

We tend to think of health as the absence of things going wrong, but biology says something else. Proteins can misfold, DNA can be damaged, and cell membranes can be destroyed, yet we remain alive and healthy, at least most of the time. Our bodies are always being disturbed, but they are also constantly responding.  Maybe, then, health is not a state of perfection, but the capacity for correction. This distinction is central to aging research, which was the focus of my summer in Sutphin Lab as a member of the Undergraduate Biology Research Program.

“Why do we age?” is still hotly debated, but “What is aging?” is maybe easier to understand. It is the progressive loss of an organism's ability to preserve normal function. The 12 hallmarks of aging, a framework for understanding the processes that drive aging, include the decline of several damage-response mechanisms as key indicators of biological decline. Even a young, healthy organism is constantly being damaged. For example, heat or oxidative stress causes proteins to misfold. Our cells, in turn, respond in a number of ways: heat shock proteins can help proteins refold, ubiquitin can tag damaged proteins to be degraded by the proteasome, and damaged cellular cargo can be packaged and degraded through autophagy. When these mechanisms fail, damaged proteins accumulate, clump together, and damage important cellular components, thereby “driving” aging. Protein misfolding is just one example. There are about a million other ways that our cells can be damaged, and an equally absurd number of systems that work to prevent this damage from translating into unhealthiness. 

What has surprised me about looking into these systems is how little being healthy resembles a stable, undisturbed state. As a kid, I thought that health at the cellular level was the default, and when things went wrong, that's unhealthiness. It's sort of the opposite, though. Things are always going wrong.

This idea has stuck with me outside of biology as well. “Things always go wrong” sounds pessimistic, and it kind of is, but it's important to remember that some level of failure is inevitable. What matters more is what you do next. It may sound intuitive, but it's easy to get caught up in the imperfections of whatever you're doing and disregard your own agency. 

Doing biology research has made this process feel much less abstract to me. Research is almost never a straightforward series of breakthroughs, and working with living things is especially unpredictable. Random experimental issues are almost inevitable. It seems like every week we have some external factor, like humidity, interfering with an experiment in some way. It's upsetting, but failed experiments and abandoned hypotheses are a part of the process. Successful research is not about avoiding these failures, but responding to them. In that sense, there is a connection between the biology I study and the way I want to study it. Just as the health of a cell depends on its ability to respond to stress, the effectiveness of a researcher depends in part on the ability to respond to the inevitable failures of experimentation.

There are more similarities as well. In some cases, a small amount of stress can actually make an organism more tolerant of future stress. This is called hormesis. Caloric restriction, for instance, is one of the most reliable “anti-aging” strategies in model organisms. When nutrients are scarce, stress response pathways like autophagy are activated, increasing cellular resistance. It's not hard to see the parallel to everyday life. Manageable challenges force us to adapt and improve. Of course, too much stress is bad. Exhaustion and burnout are unfortunately common, and there are instances where failure is just failure, no hidden lesson or benefit.