Every biological process requires energy, from a neuron firing to a cell making proteins, and from digesting dinner to taking a stroll. Energy flows constantly through every part of a cell, in chemical, thermal, mechanical or electromagnetic form.
The ‘astounding’ rise of semaglutide — and what’s next for weight-loss drugs
Discovering the molecular processes associated with this energy flow has led to fields of research dedicated to metabolism. Still, much of the biomedical research literature omits explicit considerations of energy dynamics in health and disease, focusing instead on genes, proteins and molecular mechanisms.
In our view, more biomedical scientists should pay attention to energy. Why? Because a focus on molecules is not enough to help us to understand what underpins biological processes and diseases. Both a cadaver and a thinking, feeling, living person are made up of molecules, cells, tissues and organs — the fundamental distinguishing factor is energy flow.
Molecular pathways that control diverse aspects of biology vary between individuals and between species because they are underpinned by genetics. It is no surprise, then, that molecular mechanisms of disease found in mice, fruit flies, zebrafish and other model systems often fail to hold up when studied in humans.
By contrast, the behaviour of energy in living systems follows several first principles from physics that apply across species more generally.
Take the metabolic theory of ecology, which explains why cells in large mammals burn energy more slowly than do cells in smaller ones. Simply put, nutrient and oxygen supplies are limited by fundamental physical constraints1. Oxygen-carrying blood cells, for instance, must be pumped through vascular tubes that face hydraulic resistance — it takes longer for blood cells to travel optimally through a larger body than through a smaller one.
Losing weight through better sleep
This general principle has been used to explain many physiological, ecological and evolutionary phenomena for which answers are not just written in genes2. For example, it can explain why most large animals live longer and reproduce more slowly than do smaller ones.
To encourage debate, here we speculate on how making energy dynamics a central focus of biomedical studies might help researchers to unearth a fundamental layer of biological regulation that underlies health and goes awry in disease. Biologists should get into the habit of asking simple questions, such as ‘how much energy does this cost?’.
Energy constraints
In our view, developing a theoretical framework of ‘energy constraints’ is a promising way to learn more about the underpinnings of health and disease in a way that translates across species.
This framework1–3 describes how organisms allocate their finite energy budgets to various cellular, physiological and behavioural processes. It rests on two facts, both of which have been accepted for decades.
First, every organism’s energy budget is limited3 — it’s impossible for eating ever more food to produce infinitely more energy. Scaling arguments based on physical constraints, such as hydraulics, tell us that rates of energy supply to an organism are already optimized. And data show that the ability of organisms to dissipate thermal energy could, under some conditions, be part of why living beings can’t increasingly speed up their metabolism4.
Second, organisms require specific amounts of energy for each function and system that cannot be reduced easily. The brain might need 20% of the body’s total energy supply to keep functioning, digesting food might cost 10–15% and so on. The total energy cost of all body functions, each running at maximum capacity, would be greater than the overall energy budget.
Finite energy resources mean that the body cannot keep going without resting.Credit: Kevin Liles/Sports Illustrated/Getty
Taking both points together, it follows that not all of the body’s systems can be ‘on’ at once. Organisms must continually divide finite energy resources between cellular functions, organs and behaviours. If an individual process needs more energy than usual, that energy has to be ‘stolen’ from other processes. Those decisions are called energy trade-offs.
Proponents of energy-constraint theories have begun to gather evidence that such a framework could explain a range of physiological phenomena3. For instance, healthy young female athletes sometimes stop menstruating when their training regime becomes too intense. Studies suggest that the body’s finite energy budget might be allocated to performance in a trade-off with reproduction5.
How your brain controls ageing — and why zombie cells could be key
Similarly, energy constraints might explain why a group of Shuar Amazonian children who were exposed to viral and parasitic pathogens throughout childhood experienced stunted growth6. Having one’s immune system activated constantly over years might require that less energy is expended on processes associated with optimal growth.
Moreover, when a person’s immune system is activated by a virus, they might feel ill, want to stay at home rather than socialize and experience low moods temporarily. The immune system is consuming extra energy to fight off the virus, potentially stealing energy from other body functions7 — a phenomenon well described in animal models.
Moving the needle
In our view, any process — from ageing to the growth of cancers — that takes a non-negligible amount of energy might be driven not just by molecular changes, but also by such energetic considerations. If researchers approach their system of study by asking key questions about its energetics (see ‘An energetic lens on biomedicine’), they might be able to uncover fresh targets for disease prevention and treatment.
An energetic lens on biomedicine
Some simple questions can help scientists to consider their system of study in terms of the energy trade-offs that might be involved. Here are five examples.
• What are the energy costs of this function or disease?
• Which other processes are simultaneously competing for the finite energy budget?
• Could this trait be driven by energy constraints or trade-offs?
• How much energy do the side effects of this treatment cost?
• What patient behaviours might compete with the energetic costs of healing?
Many scientists would push back on the idea of reframing all diseases around bioenergetics, given that molecular mechanisms have transformed our understanding of biology. We agree. Without molecular studies, humanity wouldn’t have drugs to treat infections, weaken some types of cancer and dissolve blood clots after a stroke. Such work will continue to be crucial for both basic biology and medicine.
But there are areas in which a wealth of expensive molecular investigations has yet to lead to effective treatments (including for Alzheimer’s disease, mental-health conditions and some cancer types), pointing to a need to consider other avenues, too. In time, we think that a person’s energy status could be considered a dimension of their health, in much the same way that a doctor might currently consider the impact of any nutrient deficiencies or genetic mutations before beginning treatment.
