The Adaptation-Maladaptation Framework of Aging

While a great deal is known about the ways in which old tissues differ from young tissues, there remains considerable room to theorize on how exactly aging is caused and progresses. Which manifestations are causative, and which downstream consequences, which mechanisms are important, which are side-effects or diversions. Theories of aging abound, alongside frameworks intended to steer thinking about aging. We stand in the opening years of a new era of medicine, in which the first rejuvenation therapies exist or are under development, senolytics that can clear senescent cells, alongside reprogramming strategies and potentially a few others. The growing attention only encourages more theorizing, but the practical development of therapies targeting specific mechanisms of aging will be the path to greater knowledge. Only by addressing a specific mechanism of aging and observing the results can we rapidly determine whether or not it is important.

The adaptation-maladaptation framework of aging posits that a cornerstone of aging is a decrease in the ratio of beneficial adaptation (Ab) to harmful adaptation (Ah) at several organizational levels of the organism, from cells to cell networks to the whole body. Decreases in Ab lead to lowered capacities in physiological adaptation functions such as learning and memory, immune system plasticity, and muscle anabolism, whereas increases in Ah promote dysfunctional metabolic remodeling, cancer, autoimmunity, and pathological cardiovascular remodeling, among others.

Certain adaptation mechanisms such as adaptive transcription can be involved in protection against aging as well as driving aging-related pathologies. Thus, aging-related decline might be inevitable but not necessarily due to random accumulation of damage over time but because adaptive mechanisms will, one way or the other, lead to progressive dysfunction (e.g., either through "directed" damage as part of adaptation or through maladaptation). Because aging is at least partly an active process, it might be possible to counteract it if we understand how biological goal states can be influenced and how adaptation mechanisms can be directed. To do so, we need to study the underlying molecular signaling dynamics in greater detail beyond mere upregulation or downregulation and beyond simple association studies.

Studying aging from the perspective of the adaptation-maladaptation dilemma with the central phenotype of a reduction in Ab/Ah opens up new experimental and theoretical approaches to study longevity mechanisms.