How to Translate Time? The Temporal Aspect of Human and Rodent Biology

Therapeutic interventions can only be effective when administered during their specific " therapeutic window. " A multitude of clinical trials based on highly successful preclinical studies performed mostly in rodents have failed to translate into similarly successful clinical outcomes (1–4). One potentially important but largely ignored factor contributing to these fiascoes is the different biological timescales of rodents versus humans. Here, I compare the rodent and human timescales of major biological events and show that while the timescales of biochemical processes such as enzyme kinetics might be comparable, more complex biological processes such as gestation, sexual maturation, lifespan, etc., run on vastly different timescales in rodents compared to humans. These comparisons strongly indicate that a " rat hour " or " rat day " is also not equivalent to a " human hour " or " human day " —and vice versa—when it comes to clinically relevant complex pathologies, such as sepsis, or inflammation (5). Rodent models of normal biology and diseases are the backbone of modern biomedical research. Species differences have been documented (6), and our lack of understanding between the timescales of rodent and human physiological and pathological processes has been raised during various scientific meetings. Earlier papers have discussed the time differences between rodents and human (7, 8). However, to our knowledge, this is the first paper that summarizes available data about time differences in normal biological processes between the two species in a comprehensive manner. Pathological processes, especially in case of acute CNS disorders such as traumatic brain injury or stroke, can change rapidly over time so the therapeutic window can be easily missed. One potentially important, but mostly ignored factor contributing to the failed translations of experimental findings into clinical practice is the different biological timescales of rodents versus humans. The simplest biochemical process, such as enzyme kinetics, is on a similar timescale in rodents and in humans (9–11). However, as complexity of the biological process grows, the differences between the timescales of the two species also grow (Table 1). For example, m/tRNA turnover is ~2.5 times faster in rodents (rat) than in humans, whereas protein turnover is ~10 times faster in rodents (12–15). Basal metabolic rate (BMR) is defined as " the minimal rate of energy expenditure per unit time by endothermic animals at rest " (16). The BMR in rats is 8 W/kg as opposed to 1.25 W/kg in humans; in other words, …