The Universal Role of Adaptive Transcription in Health and Disease

Abstract

In mammals, adaptive transcription is a crucial mechanism to connect environmental stimulation to changes in gene expression and subsequent organism remodeling. Adaptive transcriptional programs are central to various organism functions, such as learning and memory, immune system plasticity and muscular remodeling, and their activation increases cellular resilience and prevents various diseases. Yet, they also form the basis for many maladaptive processes and are crucially involved in the progression of addiction, depression, cancer, cardiovascular disorders, autoimmune conditions and metabolic dysfunction among others. They are implicated in mediating the therapeutic effects of major treatment modalities such as antidepressants and can have negative effects on treatment efforts such as in radiotherapy resistance in cancer. The present work examines the universal role of adaptive transcription as a mechanism for the induction of cell state transitions in health and disease and explores how some of humanity’s gravest disorders can be seen as adaptive logic errors. It also considers underlying principles in the basic structure of adaptive transcriptional programs such as their division into a core and a directional program and analyses how one might best reprogram cells via complex stimulation patterns to achieve concrete adaptation goals and optimal health of the whole organism.

Aging as a Consequence of the Adaptation–Maladaptation Dilemma

“…First, it explains why certain processes and molecules are implicated in both protection against aging-related decline as well as in driving aging, such as activity of CREB, Fos, and other adaptation genes (see above and previous work [1,69] ). After all, why would the deletion of genes that mediate resilience to stress and increase adaptability (e.g., positive memory regulators) cause an extended lifespan?…”

“…Many adaptive transcription mechanisms whose activation is associated with pro-longevity effects [68] are simultaneously associated with aging-related disorders such as cancer and metabolic dysregulation. [69] If we consider that different molecular activation patterns can lead to very different outcomes (e.g., sustained ERK activation drives differentiation while transient activation drives proliferation in certain cells [70] ), we see that signaling dynamics might be an important regulating factor in the adaptation-maladaptation dilemma of aging.…”

“…This illustrates the need for more detailed stratification. CREB and other pathways oftentimes have context-specific co-regulators that are activated differentially according to tissue and stimulus type (see a previous discussion for details [69] ). Furthermore, the effect of many molecules within the organism depends on the underlying signaling dynamics such as maximum amplitude and time-course of activation.…”

Aging, adaptation and maladaptation

“…Conversely, many adaptive processes are misdirected in age-related disorders leading to an increase in Ah, with for instance adaptive transcription being involved in maladaptations such as cancer, metabolic dysregulation and autoimmunity ( Lissek, 2022b ). A central feature of cancer is the remarkable adaptability of cancer cells ( Hanahan and Weinberg, 2011 ).…”

“…Thus, aging could potentially be reprogrammed and slowed down if one could decode adaptation goal states at various levels (cells, cell networks, organs, etc. ) and understand how to direct, restrict and boost adaptation processes which has been previously discussed ( Lissek, 2022b ).…”