A Tour of Some of the Molecular Damage Involved in Aging

The intricate molecular machinery found in cells only functions correctly when it is undamaged, meaning formed of the right atoms and bonds, and that often sizable structure correctly arranged into a particular three-dimensional shape. A cell is essentially a liquid bag of molecules that are constantly coming into contact with one another, however. Large numbers of these molecules react in inappropriate ways or become misfolded, and so a cell incorporates layer upon layer of quality control mechanisms, each of which strives to ensure that cellular machinery remains correct in form and structure. Broken parts are aggressively removed and recycled, but nonetheless some damage inevitably slips through. Aging itself is essentially a process of damage accumulation, at root an accumulation of unwanted and malformed molecules, and then the chain of unfortunate consequences that follows from that state of damage. This open access review covers some of the forms of molecular damage involved in the aging process:

The idea that aging results from the gradual accumulation of molecular damage is deeply rooted in the aging research field, although it can appear in verbal disguises so different as to seem conceptually independent. However, damage is implicit to DNA in the somatic mutation theory of aging, to the extracellular matrix proteins in the cross-linking theory, and to phospholipids in the membrane theory. The free-radical theory implies that reactive oxygen species (ROS) are responsible for damage, and the carbonyl-stress theory blames free carbonyls for it. With regard to the last two theories, the former celebrates its 60th anniversary this year and remains the most influential in the "damage field", and the latter is its extension insofar as it attributes the origin of many of the most noxious molecular species to the free-radical oxidation of metabolites initially devoid of highly reactive carbonyl moieties.

In a metabolic system, not only spontaneous decay and degradation reactions, such as hydrolysis, oxidation, and racemization, but also spontaneous multistage synthetic processes take place. Can the products formed in this way be regarded as metabolites in a strict sense? They are not generated by enzymes, are not used purposefully, and are often hazardous. One way to view them is as damaged metabolites. For example, 5-Scysteinyldopamine is a damaged form of cysteine or dopamine. A related way to conceptualize this phenomenon is to view it as a sort of 'underside' of metabolism or 'parametabolism'. A conceptually similar but more general approach is to regard such unwanted products as a manifestation of the imperfectness of metabolism and its components, which together produce deleterious effects at all levels of biological organization. The totality of such effects has been described as the "deleteriome", which expands with age and represents the biological age of an organism. One way to increasing the deleteriome is by the spontaneous polymerization of damaged metabolites, such as catecholamine-derived quinones. In reality, such polymerization occurs in a milieu abundant in proteins, which are included in the resulting agglomerates, wherein they become covalently modified and misfolded and thus made prone to aggregation. Altogether, this leads to the accumulation of polymers of (damaged) metabolites associated with protein aggregates in the form of lipofuscin, neuromelanin, and other forms often referred to as waste.

A good case for applying the ideas discussed above to a specific situation is provided by bisretinyls, the major constituents of lipofuscin accumulated in the pigmented epithelium of the eye. Bisretinyls are byproducts of visual cycle biochemistry. Without delving into important details and conflicting views, it is sufficient in the present context to point out that the functional demands of light perception ensure that the aldehyde retinal is constantly present free in an environment rich in ethanolamine moieties. The result is the formation of retinyl dimer and a host of related compounds accumulating in photoreceptor membranes, which are constantly shed off to be phagocytized by pigmented epithelium cells. The poorly degradable retinal dimer and related products form lipofuscin deposits in pigmented cells and thus increase the risk of macular degeneration, the most common form of age-related vision loss.

Several lessons follow from the above case. First, damage accumulation results from normal functions, and the pathways of damage formation may become clear only after the molecular details of normal functions become known. Second, damage manifests itself in a functionally significant manner at ages rarely achievable in the wild under the conditions in which the species in question evolved. Therefore, there was no selection pressure towards the prevention of accumulation of this sort of damage. However, there was pressure towards preventing any immediate damage, even at the expense of later adverse consequences. In fact, lipofuscin accumulation in pigmented epithelium is a consequence of clearing of photoreceptor cell membranes from damage caused by retinal liberated in the course of light perception. Third, via a series of transitions through rapidly turning-over cell constituents, damage finally accrues as a slowly turning-over material in the nonrenewable component of a functional system where the deposits of damaged metabolites accumulate.

Spontaneous chemical reactions between metabolites are often labeled with proper names, such as Schiff, Pictet-Spengler, Amadori, Mannich, or Michael, just because they are typical and will take place wherever the respective reactants come together. Thus, from the chemical point of view, a metabolic system cannot but be plagued with numerous short-circuits, leaks and other adverse concomitants of metabolism. Unwanted reactions of this sort give rise to diverse damage products that increase in number and abundance with age and are adjusted (with regard to both composition and rate of increase with age) by interventions that affect lifespan. These reactions in their entirety are sufficient to cause what is generally termed aging.

Link: http://www.jbc.org/cgi/doi/10.1074/jbc.R116.751164


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