Physiological programming, adaptation, and regeneration

Physiologically occurring programming processes, inherent within biological systems, govern the development and function of organisms. Driven by genetic and epigenetic factors, these processes dictate cellular differentiation, organ development, and physiological responses. Understanding the intricacies of natural biological programming offers insights into how cells and tissues self-organize, adapt, and repair, with a perspective toward advances in regenerative medicine, disease prevention, and therapeutic innovation. A better understanding of these intrinsic programming mechanisms may, in the future, enable novel biomedical applications.

Foetal metabolic programming and metabolic maturation are interconnected processes that shape an individual's metabolic health from early development through adulthood.¹

Foetal metabolic programming, a critical concept in developmental biology, examines how environmental factors during pregnancy influence the long-term health and disease susceptibility of the offspring.² This field investigates the mechanisms by which prenatal exposures, such as nutrition, stress, and toxins, can alter foetal development,³ potentially leading to chronic conditions such as obesity, diabetes, and cardiovascular disease later in life.⁴ Gestational diabetes mellitus is an acquired glucose intolerance with onset or first detection during pregnancy. It affects up to a fifth of all pregnant women and usually disappears after delivery.⁵ Foetal exposure to maternal gestational diabetes increases the risk of a multitude of adverse health outcomes for both mother and child, and is probably modified by maternal body weight. Therefore, improving glucose and weight control during pregnancy or before conception could reduce the risk to the offspring.⁶ Weight control during pregnancy is mostly relevant for women who either are obese when they get pregnant, or who gain weight too quickly during pregnancy. While a pregnant woman should not go on a diet or try to lose weight during pregnancy, a focus on healthy nutrition and physical activity is helpful. Data indicate that obese women before pregnancy may benefit from recommendations regarding, for example, time-restricted eating^{7, 8} and avoiding specific obesogenic habits such as late-night snacking⁹ or sedentary lifestyle choices.¹⁰ As current data also indicate a differential benefit of exercise for weight control at specific times during the day¹¹ and an influence of exercise-induced organ crosstalk on energy metabolism,¹² more data are needed to give specific recommendations for tailoring lifestyle interventions to the needs of this specific demographic. Understanding foetal programming and its impact on health outcomes may pave the way for preventative strategies and early interventions to improve lifelong health.

The term metabolic programming often, but not always, refers to foetal metabolic programming, but is sometimes also used differently, for example, to describe how, in general, genomic mechanisms govern metabolic physiology,¹³ or how specific subsets of cells develop context-specific metabolic phenotypes.¹⁴ Li et al. for example, describe how metabolic programming in collagen matrix production affects organ fibrosis.¹⁵ Other remodeling processes in which cellular metabolic mechanisms change include cardiac remodeling with potential arrhythmogenic consequences¹⁶ and renal remodeling promoted by cells of the renin lineage following urinary tract obstruction in neonates.¹⁷

Metabolic maturation refers to the developmental process, which encompasses the progressive refinement and optimization of metabolic pathways as an individual grows, by which an organism's metabolic pathways and functions become fully operational and efficient, typically progressing from an immature foetal/neonatal state to adult metabolic function capable of sustaining adult physiological activities. Metabolic plasticity and metabolic flexibility both refer to an organism's ability to adapt its metabolism to varying conditions, but regarding different aspects of this adaptability. Metabolic plasticity is often used to refer to the long-term adaptive changes in metabolism that occur in response to sustained environmental changes, such as diet, exercise, or disease conditions. It usually involves structural and functional alterations at the cellular and molecular level, including changes in gene expression, enzyme activity, and cellular architecture and often leading to permanent or semi-permanent changes in the metabolic pathways. Common examples include the adaptation to a high-fat diet leading to changes in fat metabolism, and long-term endurance training resulting in increased mitochondrial biogenesis and enhanced oxidative capacity in muscles. Metabolic flexibility, in contrast, denotes the short-term, dynamic switch between different metabolic pathways or substrates (such as carbohydrates and fats) in response to immediate changes in energy demand or nutrient availability.¹⁸ This involves rapid adjustments at the level of enzyme activity, substrate utilization, and energy production. Both metabolic plasticity and metabolic flexibility are crucial for maintaining metabolic health and responding to environmental and physiological challenges, as, for example, seen in the “omnivorous” short-term metabolic flexibility of cardiomyocytes and metabolic plasticity in adult hearts during the adaptation to, for example, endurance training.¹⁹ Key differences include timescale (long-term adaptations vs. short-term, immediate responses), the nature (structural and permanent vs. reversible and transient), and the context (response to chronic conditions vs. response to acute or immediate stimuli) of the metabolic changes that occur. Especially, cancer research often differentiates between metabolic flexibility and plasticity, defining metabolic reprogramming during tumor progression as metabolic flexibility (the ability to use different nutrients) and plasticity (the ability to process the same nutrient differently).¹⁸

In addition to physiologically running “programs,” Dokholyan et al. define programming processes as inventions that “automate[…] instructions to perform a particular task.”²⁰ Biological programming is an emerging interdisciplinary field, which merges principles of computer science with molecular biology, to design and manipulate biological systems toward a desired phenotypic output. This innovative approach thus aims at programming living cells to perform specific functions, similar to how software directs a computer. Currently, researchers are trying to estimate the translational potential of biological programming to revolutionize medical treatments, biotechnology, and synthetic biology for precise and programmable therapeutic interventions. Recently, for example, strategies emerge to use engineered bacterial strains to modulate gut microbiota in the treatment of metabolic disorders.²¹

Physiological programming processes play a pivotal role in shaping health outcomes. These processes, which involve complex interactions between genetic, environmental, and developmental factors, set the stage for an individual's physiological trajectory from early development through adulthood.

Future research should aim to elucidate the precise mechanisms of physiological programming and how these can be modulated to promote health and prevent disease. Advances in genomics, epigenetics, and systems biology offer promising avenues for deepening our understanding of these processes.²² Additionally, interdisciplinary approaches integrating clinical, environmental, and social sciences will be crucial in translating these insights into practical healthcare strategies toward a more personalized and preventive health care, ultimately improving health outcomes across populations.

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