Fight Aging!

The major divide in theories of aging lies between the mainstream camp of damage accumulation and antagonistic pleiotropy on the one hand, and the minority camp of programmed aging theories on the other. The damage accumulation camp sees aging as a side-effect of the focus of evolutionary mechanisms on early life reproductive success, favoring the development of biological systems that are front-loaded for early life success, with little investment in maintenance over time. Programmed aging purists view aging as a process that is under active natural selection, however, not a side-effect at all. Why degenerative aging would be selected for is debated, but group selection to reduce the risk of runaway population growth has been argued, as well as the winnowing effect of environmental change on non-aging species, as aging allows for faster adaptation to that change, out-competing non-aging competitor species.

The relatively recently developed hyperfunction theories of aging have a foot in each camp, and might crudely be thought of as a compromise position, though that isn't why they emerged. It has been a difficult area of the field to follow, as it wasn't always clear that everyone involved had the same view of the definition of hyperfunction. Today's open access paper provides a good summary of the consensus hyperfunction view, insofar as such a thing now exists: biological programs that determine early life growth and development continue to operate in adult life in maladaptive ways, and become overtly harmful over time, giving rise to aging. This is roughly a direct conceptual fusion of the concepts of antagonistic pleiotropy and programmed aging. Does any of this theorizing matter? To the degree that it determines research priorities for the development of therapies to treat aging, it probably does.

A brief history of the hyperfunction theory of aging and future directions

Understanding the mechanisms underlying aging processes is crucial for biogerontology and for developing translational approaches. There is much debate, however, regarding the fundamental nature and drivers of aging. The idea that aging arises from genetically encoded processes has gained traction in recent years, the so-called "programmatic theories". It is important not to conflate programmatic and programmed theories, as the latter view aging itself as an evolved adaptation serving a function, while in programmatic theories late-life decline is driven by developmental programs that run-on without aging being adaptive.

In past decades, the idea that aging results from a program or from continued developmental processes became less popular. The evolutionary theory of aging argued against a programmed (i.e., adaptive) aging process, predicting that such a program would be selected against. The dominant view was that aging arises from the declining force of natural selection with age, the so-called "selection shadow". In this model, both genetic variants with detrimental late-life effects, or variants beneficial early in life but harmful later, can become fixed in populations, contributing to aging; here, aging is not an adaptation and, in that sense, not programmed.

The increasing emphasis on molecular damage in aging research was likely driven, at least in part, by advances in molecular biology and biochemistry. The explosion of molecular discoveries in the second half of the 20th century revealed a vast and intricate number of cellular components and biological processes, which in turn led to a proliferation of theories linking aging to defects in each of these many processes. Because virtually any important biochemical or molecular process can malfunction and become harmful to cells, it is easy to conceive new damage-based theories of aging. This abundance of molecular detail reinforced the perception that aging is driven by stochastic damage and led to many theories and frameworks positing damage accumulation as the root cause of aging. It was against this trend that a new wave of programmatic theories emerged at the start of the 21st century.

In 2006, a seminal conceptual paper proposed the quasi-programmed theory of aging, introducing the term hyperfunction. It proposed "a quasi-program for aging, a continuation of the developmental program that is not turned off, is constantly on, becoming hyper-functional and damaging, causing diseases of aging." While acknowledging that damage occurs with age, it was argued that such damage plays a negligible role in determining lifespan. Instead, quasi-programs are the principal drivers of aging and limiting human lifespan.

Although programmatic theories, such as hyperfunction, provide powerful conceptual frameworks for understanding the aging process, much work remains to be done. They are still outside the dominant geroscience paradigms, such as the "hallmarks" and "pillars" of aging. The unfortunate consequence - I would argue - is that most aging studies focus exclusively on adult life, hindering efforts to connect aging to developmental processes. If aging processes follow trajectories set early in life, then studying the whole life course is imperative to elucidate aging mechanisms. Besides, if repair and maintenance mechanisms are downregulated during development, then studying early development may prove valuable for identifying rejuvenation therapies, as already demonstrated in partial reprogramming.