My encounters with the hyperfunction theory of aging have at times left me confused, and I suspect that not all of those arguing for it are working from exactly the same picture in their heads. The version presented in today's editorial is somewhat more clear, possibly because the primary intent of the paper is to clarify. It is worth noting up front that the author is very much a proponent of the centrality of mTOR and related signaling pathways in aging, in the sense that aging and age-related degeneration is a program of regulatory change that produces damage. The opposing mainstream viewpoint in the research community is that aging is an accumulation of molecular damage, and regulatory change in signaling pathways is a consequence of that damage.
Hyperfunction is (roughly) the inappropriate continuation of developmental programs past their allotted time, leading to harm to the organism. The author of the editorial below would suggest too much mTOR signaling in later life as a case in point. On the other side of the fence, accumulation of damage is, roughly, the side effect of a metabolism optimized for early life success, lacking long-term repair capabilities, such as the ability to break down persistent cross-links that accumulate only very slowly, or lacking the structural capacity for indefinite function, as is the case for the adaptive immune system, which requires ever more resources devoted to memory.
Both the hyperfunction and damage accumulation views of aging are examples of antagonistic pleiotropy, meaning a given mechanism or system that operates beneficially in youth, and then harmfully in later life. This is the guiding view of the evolution of aging because early reproduction is favored by natural selection. Early reproduction wins the evolutionary niche, up to a point, and therefore there is a race to the lower bound of success, producing organisms optimized to win the competition for early reproduction at the cost of later health. There are counterbalances to the primacy of early reproduction, such as the grandmother effect: our capacity for culture (relative to other primates) has extended human life span (relative to other primates) because grandparents can contribute to the reproductive success of their grandchildren. But on the whole, natural selection favors early reproduction, and builds systems that fall apart once that critical period is done with.
On the topic of the primacy of mTOR and related signaling: I can't say as I think that a central role for mTOR signaling as a rate-limiting cause of aging is a defensible hypothesis given the evidence. It is also not defensible to say that the outcome of the targeted removal of cell and tissue damage in mice suggests that this damage is not life-limiting. Life span in short-lived mammals is very plastic in response to regulatory changes related to the central mechanisms covering cell replication, nutrient sensing, and cell maintenance processes upregulated in response to stresses, such as autophagy. This is not the case in long-lived mammals, as illustrated by the sizable difference in the life extension produced by calorie restriction in mice (as much as 40%) versus humans (a few years at best). While mTOR inhibition has slowed aging to a similar degree to clearance of senescent cells in mice, it hasn't achieved results anywhere near as impressive as clearance of senescent cells when it comes to reversal of specific age-related conditions, such as cardiac hypertrophy. Damage accumulation and repair as rejuvenation after the SENS view of aging looks much more compelling.
The first misconception is that hyperfunction is always an increase of function. Correctly, hyperfunction is often an unchanged function, that is still higher than optimal for longevity. Hyperfunction is a function that was not switched off upon its completion. In some cases, age-related alterations are indeed an absolute increase: hyper-secretory phenotype, pro-inflammation, hypertension, hyperlipidemia, hyperglycemia, hyperinsulinemia, hyperplasia, and hypertrophy of cells and organs (e.g., heart and prostate). In typical cases, hyperfunction is relative. It may even be a decrease of function that is still higher than optimal for longevity in the aging organism.
Using an analogy, consider a car driving 65 miles per hour (mph) on the highway with a 65 mph speed limit. This is the normal and optimal speed on this highway, or optimal functioning early in life. Early in life, during organism growth, all cellular and systemic functions are optimal for growth (not for longevity). However, if the car exits the highway to enter low-speed streets without decreasing speed (stuck accelerator) and continues at the same speed, 65 mph becomes over-speeding, or hyperfunction. The car is bound to crash on your driveway and is destroyed by over-speeding. It has no chance to be destroyed on a molecular level by rusting.
The second misconception is that the hyperfunction theory of aging denies a harmful accumulation of molecular damage. To clarify, molecular damage does accumulate. Furthermore, molecular damage would eventually kill the organism, unless the organism dies from hyperfunctional aging or, even more specifically, from mTOR-driven aging. Aging due to molecular damage and due to cellular hyperfunctions occur in parallel, but the latter is a life-limiting process, which progresses faster. How do we know that hyperfunctional aging is life-limiting and accumulation of molecular damage is not? In several dozen studies, rapamycin (mTORC1 inhibitor) prolonged lifespan in animals. Then mTOR-driven aging is life-limiting almost by definition.
The third misconception is that hyperfunction theory is primarily based on an evolutionary theory. Correctly, the hyperfunction theory is principally based on a cellular model of geroconversion. The hyperfunction theory is not just an evolutionary theory, even though it is completely in agreement with the latter and develops the notion of Antagonistic Pleiotropy (AP) further. Evolutionary perspectives in the hyperfunction theory are needed mostly to explain why hyperfunctional (quasi-programmed) aging is life-limiting and why accumulation of molecular damage is not. Otherwise, the hyperfunction theory is a mechanistic theory: an analogy of the cellular model of geroconversion in vitro. When cells proliferate, mTOR and other growth-promoting signaling pathways drive cellular mass growth, which is balanced by cell division. However, if the cell cycle is blocked by p21 or p16, then the same mTOR pathway drives "pathological growth" (geroconversion) from reversible arrest to irreversible senescence. Geroconversion is a continuation of growth - a quasi-program of growth.
The hyperfunction theory is a translation of the rules of geroconversion to the organism. Organismal aging and geroconversion can be described in similar terms, and similar signaling pathways drive geroconversion and organismal aging. It does not necessarily mean that a few senescent cells cause organismal aging. Fully senescent cells may contribute to aging, but are not required. Instead, most cells are becoming at least relatively hyperfunctional, gerogenic, producing age-related diseases.