The Energy Paradox¶

The Energy Paradox

We all know you need energy to survive. Food contains macromolecules -- proteins, lipids, and carbohydrates -- that have chemical energy, which we measure as calories. Your cells break down these molecules, using the energy to perform cellular processes. Everything from DNA replication to muscle contraction to the synthesis of all the protein machines that perform these processes requires calories. Every living thing uses ATP for these energy transactions, but there are a number of ways to get the energy to create ATP. Eukaryotes, including all plants, fungi, and animals, have mitochondria, which use a process called aerobic respiration. "Aerobic" meaning "in the presence of oxygen," because the steps to release energy from food molecules and create ATP use oxygen to "burn" the molecules. This process is fundamental to all multicellular life. Even plants, which use photosynthesis to assemble their own food molecules (releasing oxygen as they go), still have to reverse that process through aerobic respiration to create ATP. The crux of what I call the "energy paradox" is as follows: although we fundamentally need those calories for our survival, the very process of metabolizing those food molecules is intrinsically harmful to cells, accelerates aging, and contributes significantly to mortality. We've known for decades that lab rats allowed to eat as much as they want live substantially shorter lives than rats with a restricted diet. This effect on average lifespan is somewhat mitigated by exercise and reduction in body mass, but notably, not their maximum lifespan. In other words, the decline in maximum lifespan is not an effect of obesity, but a direct function of caloric intake. Animals on restricted calorie diets live longer, regardless of their level of activity.

(To a point, obviously. Starvation still kills you.) Studies that compared rats on restricted calorie diets, who either exercised or received even fewer calories, such that their body masses stayed the same, found no difference in their lifespans. Whether they exercised or not, they lived longer than unrestricted counterparts. https://t.co/WVTeeHCmj8 So what does this mean? Why does eating less extend lifespan, even in sedentary animals? There are a number of hypotheses.

One is the idea that aerobic respiration results in the creation of reactive oxygen species -- oxygen-containing molecules which react with other molecules. Molecules such as the proteins, lipids, and especially DNA that your cells need to function. Oxygen is a very reactive element, which is why it's useful for reacting with food molecules to release energy. ROS's are produced as a byproduct of respiration and wreak havoc on cells. They react with and break apart DNA, causing damage that can't always be repaired. If allowed to go on unchecked, this will eventually lead to an accumulation of mutations that can cause cells to become cancerous. To deal with this, cells use antioxidants, which "soak up" ROS's. But antioxidants aren't perfect, so some ROS's will still break through that first line of defense, at an increasing rate as more food gets metabolized. The second line of defense is DNA damage repair, which, again, is not perfect. Eventually, the damage would outpace repair. The next line of defense isn't about protecting the cell itself, but the whole organism. To head off the possibility of a cell turning cancerous, cells undergo apoptosis -- programmed cell death. ROS's themselves are actually used as one of the signals to initiate apoptosis. (This is handy, because the thing causing the problem triggers the solution to the problem. This is a common thing across a whole bunch of other biological processes, such as pieces of pathogens triggering the immune responses to those pathogens.) Obviously, there are a bunch of other things that can cause cells to become so damaged that they might become a problem, and many other pathways to trigger apoptosis. But again, these regulatory checkpoints aren't perfect, which is why, given enough time, you will develop cancer. Cancer is such a huge concern for multicellular organisms that it's practically our bodies' chief preoccupation. Our cells would do just about anything to prevent cancer, including killing themselves and each other. But one thing they simply cannot do is stop consuming calories. Over the course of your life, every calorie you consume to survive generates more and more ROS's. Each line of defense gets slowly overwhelmed over time. Apoptosis has to increase to compensate. Eventually, cell death starts to outpace the growth of new cells to replace them. This is one of the primary ways in which aging occurs. Wrinkles form as the collagen- and elastin-producing cells in your dermis thin out. Bones get weaker as osteoblasts age out. Muscles shrink, your immune system gets depleted, and whole organs eventually shut down. Obviously, there are a lot of other factors at play in aging, cancer, metabolism, and mortality. There are many hypotheses about the relationship between caloric intake and lifespan. The oxidative damage model is my favorite, but it still presents a lot of questions. Chief among them is the fact that, as mentioned, every eukaryote uses aerobic respiration for energy. If it's so hazardous, and such a universal problem, how can evolutionary solutions to it be so rare?

One answer is, of course, that the status quo is good enough. Oxidative damage accumulates over a long period of time. So long as organisms can survive it long enough to reproduce, there's no real selective pressure that would give organisms a relative advantage for being able to prevent it. This would be true for any other cause of aging. An answer more specific to ROS's is that signaling I mentioned earlier. ROS signaling is used for a lot more than just triggering apoptosis, and it is an incredibly ancient toolkit across all multicellular life. Tampering with ROS's too much impairs development and cell growth. So we're kind of stuck with it. This dialectical tension between the acquisition of energy and the damage wrought by its acquisition is largely inescapable. We can't resolve the fundamental contradiction without running afoul of the systems built up around that tension. There might be some perfect balance of cellular mechanisms that would maintain those signaling pathways, while preventing or unerringly repairing the collateral damage. But evolution is stupid, and cannot plan ahead. Maybe someday, we intelligent beings can.