Fight Aging!

Aging is the accumulation of molecular damage and the consequences of that damage. This molecular damage and its immediate consequences are comparatively simple to describe, but the damage takes place in a fantastically complex system of cells, cellular interactions, tissues, organs, organ interactions, and more. Every problem causes cascading, interacting chains of cause and effect, hard to pick apart via inspection and hard to reason about. Cellular metabolism and tissue structure and function are far from fully mapped, and aging involves sweeping changes throughout the organism and its countless subsystems.

Today's open access paper is an interesting attempt to layer the known hallmarks of aging (which are not all necessarily deeper causes of aging) by how they emerged over time in the evolution of life from unicellular to multicellular and higher organisms. This may well be a useful mental tool when considering the merits of various approaches to the treatment aging, but again, the system as a whole is fundamentally hard to reason about.

The enormous complexity and incomplete understanding of the overlap between aging and cellular biochemistry is why many people are in favor of repair-based interventions as the most effective path forward. There is a better understanding of root causes in aging than there is of how these causes connect in detail to the end consequences of aging. This produces an environment in which the most cost-effective approach is to repair a form of fundamental cell and tissue damage, and see whether or not it produces impressive results in animal studies. Then figure out the details regarding how and why it produces impressive results.

This is how the present focus on senolytic therapies to clear senescent cells emerged. Prior to producing the first demonstration studies of senescent cell removal in mice, not even the researchers who suggested this as a promising line of work thought that this approach to aging would produce rejuvenation in mice to the degree that it does. The exploration of why and how this is so beneficial will take considerably longer than the process of bringing the first useful senolytics into widespread use. Aging is hard to reason about.

The Evolution of the Hallmarks of Aging

The evolutionary theory of aging has set the foundations for a comprehensive understanding of aging. The biology of aging has listed and described the "hallmarks of aging," i.e., cellular and molecular mechanisms involved in human aging. The present paper is the first to infer the order of appearance of the hallmarks of bilaterian and thereby human aging throughout evolution from their presence in progressively narrower clades. Its first result is that all organisms, even non-senescent, have to deal with at least one mechanism of aging - the progressive accumulation of misfolded or unstable proteins. Due to their cumulation, these mechanisms are called "layers of aging."

The first layer of aging is the accumulation of unfolded or unstable proteins. As it appears as early as in unicellular organisms, it is universal. In other terms, no species is devoid of at least one mechanism of aging, although in some, its effects are efficiently countered by mechanisms of anti-aging. The first mechanism of anti-aging is disposal of unfolded or unstable proteins by cell division.

The second layer of aging is epigenetic alterations under the form of chromatin remodeling and histone modifications. It has appeared with the evolution of a more sophisticated support for DNA and does not seem to be causally related to the first layer. It concerns all archaea and eukaryotes.

The third layer of aging contains mitochondrial dysfunction, more specifically, ROS damage and the progressive degradation of mitochondrial integrity and biogenesis, damage to mitochondrial DNA and damage to the nuclear architecture, and finally the progressive degradation of proteolytic systems. The appearance of these mechanisms of aging is apparently unrelated to the existence of the previous ones. Yet, interactions are likely: the generation of ROS may increase the number of misshaped proteins, the loss of mitochondrial integrity may increase the generation of ROS. The mechanisms of the third layer result from the appearance of the characteristics of eukaryotic life, the existence of a nucleus, of mitochondria (and chloroplasts), and the appearance of autophagy. All eukaryotes share the mechanisms of this third layer - except those who have possibly lost one of its components.

The fourth layer of aging contains all the mechanisms grouped under the label of 'nutrient sensing': sirtuins and the TOR, AMPK and Insulin - IGF-1 pathways. These mechanisms also appeared independently from mechanisms of the first three layers. However, the level of interactions increases dramatically with this layer, which may be interpreted as a mechanism focused on the management of the available energy sources that happens to control many of the mechanisms of aging of the first three layers (directly with the regulation of autophagy or mitochondrial activity, indirectly through the double role of sirtuins in the regulation of this mechanism and in genomic maintenance), and thereby modulate the rate of aging. These mechanisms characterize opisthokonts, but not all eukaryotes, as their components do not seem to be involved in aging in bikonts, although most of them are present.

These first four layers of aging together constitute the hallmarks of unicellular aging. Unicellular organisms contain some or all of them and most multicellular opisthokonts still contain all of them. In unicellular organisms, the problem of unicellular aging is mainly solved through reproduction, sexual or clonal, which resets the aging clock for at least one of the two cells that result from cell division.

The fifth layer of aging contains DNA methylation and transcriptional alterations. In general, these epigenetic mechanisms, appeared early during the evolution of unicellular organism, have the effect of modulating the expression of genes in a cell, which is necessary to the coordination of individual cells in multicellular life. There is evidence that they are involved as mechanisms of aging in metazoans but it is plausible that they are involved in the aging of a colony in holozoans.

The sixth layer of aging is the decline in the regenerative potential of tissues. It appears with the distinction between stem cells and somatic cells in metazoans. Importantly, this duality of cells is an elegant multicellular solution to the problems of unicellular aging, as long as damaged somatic cells can be renewed, and as the renewal of stem cells can outpace the accumulation of damage as efficiently as prokaryotes get rid of accumulated protein aggregates by sequestrating them into one lineage. When the renewal of cells is insufficient, multicellular organisms age.

The seventh layer of aging contains both inflammation and the accumulation of senescent cells. The mechanisms of aging in this layer are likely to be strongly dependent on the existence of a lower rate of renewal of the cells in a multicellular organism, although they probably originate in some of the specificities of eumetazoans. Inflammation, cell senescence, and the decline in the regenerative potential of tissues together form the engine of aging in most senescent multicellular organisms.

The eighth and last layer of aging contains the accumulation of mutations in nuclear DNA, telomere attrition, and alterations of other forms of intercellular communications as those involved in inflammation. These mechanisms of aging do not depend on the appearance of new entities with bilaterians, but on the considerable complexification of intercellular communication and mutual dependency that appears at this stage, under the constraint of the existence of a complex organization.

The last four layers of aging together constitute the hallmarks of metacellular aging, that is, the aging of the cells of the organism that happens in multicellular life only. Metacellular aging is the problem of aging left unsolved by evolution in many metazoans. It basically consists in the failure to control the effects of unicellular aging, so that they progressively affect the whole multicellular organism, which eventually dies.

In the end, although the multilayer view of aging casts considerable light on the general process of aging, there are three important limitations, that all stem from the essentially 'basic cell biology' approach to aging. The first is that it ignores potentially important non-cellular factors of multicellular aging, like the continuous remodeling, and progressive structural degradation, of the extracellular matrix. The second is that it does not describe how variations of the general mechanism of aging explain the huge variety of the rate of aging among bilaterians. The third is that the importance, and maybe even the implication of some mechanisms of aging may depend on environmental factors.