Fight Aging!

The myriad mechanisms of cellular biology are a seething pool of feedback loops and interactions. Every protein that plays a role has half a dozen other roles on the side: evolution produces promiscuous reuse of every new component that arises. Thus little if anything happens in isolation in our cells, and changes produce reactions. So when we say that degeneration in aging is produced by the accumulation of a variety of forms of damage, we refer to a very complicated progress that spirals out from comparatively simple beginnings. Consider the SENS model for the causes of aging, for example. Broadly, the operation of metabolism produces waste byproducts that are not always entirely cleaned up or recycled. Separately, some important cellular components can become damaged in the course of normal operation in ways that resist the otherwise highly efficient recycling machinery. Further, evolution has adapted certain quiescent cell states used in embryonic development into a way to resist cancer. These senescent cells behave in ways that may well suppress cancer risk in the short term, but are not good at all for tissues over the long term. Separately again, some larger and more complex structures, such as the thymus or the immune system considered as a whole, become misconfigured or less useful over the course of time as an inevitable consequence of their structure and modes of operation. Even if all of their cellular components continued to work perfectly in and of themselves, some of our biological systems cannot operate well indefinitely.

These are all discrete sources of damage and gradual failure, distinct processes and harms that must be addressed separately by any suite of rejuvenation treatments. Damage doesn't accumulate in isolation, however. The harms interact. Persistent metabolic waste products degrade the effectiveness of cellular recycling systems, for example, and that probably exacerbates other sources of damage that arise from damaged cell components, misfolded proteins, and the like. There are many other examples of the way in which forms of damage might interact with one other, but there is also a lot of room for theory and speculation, since a complete map is lacked of the detailed progression of aging from its root causes through to age-related disease and death. Researchers have a catalog of the simple forms of damage at the beginning of the road, a catalog of complex diseases at the end of the picture, and only the first sketches of the story in between. Fortunately, if you have the catalog of damage you don't need the full picture in order to build treatments based on repair. Unfortunately the majority of the scientific community is more interested in filling in the gaps in the picture than in producing treatments.

As to speculation: given the list of forms of damage outlined in the SENS vision of aging, it is interesting to consider which of them are working in concert. If mitochondrial DNA damage was repaired throughout the body, would it result in diminished levels of misbehaving senescent cells, for example? Generally cells become senescent in response to a tissue environment that appears more damaged, or in response to the presence of toxins that might have that effect. Does the presently partially understood set of influences include the state of mitochondrial damage in a straightforward way? That is hard to tell in absence of good ways to control that damage experimentally. The fastest approach to answering this sort of question at the present point in time is probably to implement mitochondrial repair treatments in mice and see what happens.

Mitochondrial effectors of cellular senescence: beyond the free radical theory of aging

Cellular senescence is a process that results from a variety of stresses, leading to a state of irreversible growth arrest. Senescent cells accumulate during aging and have been implicated in promoting a variety of age-related diseases. Mitochondrial stress is an effective inducer of cellular senescence, but the mechanisms by which mitochondria regulate permanent cell growth arrest are largely unexplored.

The free radical theory of aging has been adapted to the study of cellular senescence. Many studies show that reactive oxygen species (ROS) can induce cellular senescence. Indeed, hydrogen peroxide (H2O2), which is considered as the major ROS within the cell, is a potent inducer of cellular senescence in many cell types. While exogenous treatment with H2O2 can promote cellular senescence, endogenous ROS (such as superoxides and hydroxyl radicals) is also implicated in the establishment and maintenance of the irreversible growth arrest.

While several studies implicate the role of ROS during cellular senescence, others also suggest that mitochondrial ROS generation may not necessarily be the primary cause of cellular senescence. One [study] suggests that increased mitochondrial ROS production in replicative senescent cells is a consequence of the senescence phenotype rather than the reverse. Because mitochondria influence many cellular processes, accumulation of mitochondrial oxidative damage, as proposed in the free radical theory of aging, may be an oversimplification of the signaling mechanisms involved in the establishment of cellular senescence. It is also possible that mitochondrial ROS can act as signaling molecules to trigger cellular senescence, independent of mitochondrial oxidative damage, although this hypothesis still needs to be proven.

It is then necessary to go beyond the free radical theory and examine other mitochondrial effectors that may be involved in the irreversible cell growth arrest. Multiple mitochondrial factors, such as excessive mitochondrial ROS production, aberrant mitochondrial dynamics, defective electron transport chain, imbalanced bioenergetics, activated AMPK, decreased NAD+ levels, altered metabolism, and dysregulated mitochondrial calcium homeostasis, contribute to the establishment of irreversible growth arrest. All of these different mitochondrial signaling pathways can regulate each other, but how these factors cooperate to promote cellular senescence, and whether these pathways are conserved in all senescent cells still remains unclear.

As you can probably tell, this is one of those "look at all these things we don't know yet!" papers. I see a lot of these day in and day out. There is indeed a great deal that is still a big blank space on the map of how exactly we age, and that is exactly why more of a focus should be placed on the development of repair technologies based on what is presently well known.