Inter-Relationships of Aging Theories
“The theories of aging are neither complete, independent nor final. Aging is not a simple process and there is much signalling between systems in the body. So all of the theories of aging covered here are part of a more comprehensive systems-oriented theory yet to be clarified. The age-related epigenetic signaling involving changing hormone levels, oxidative damage, glycation and lipofuscin generation and removal is complex and not yet well understood. Signals originating in the mitochondria affect DNA expression and visa-versa. Cancer and inflammation have a close relationship as do oxidative damage and tissue glycation. There is without doubt much interplay between the programmed mechanisms of aging and the presence of cell damage. It may require 30 or more years for a fairly complete systems perspective of what constitutes aging and the diseases of aging to emerge. In the interim, selected pieces of the picture are becoming clear and it seems that every few days or weeks a new piece of the puzzle is revealed.
As a way of summary, here is a first cut of how the theories of aging relate to each other. The most general theory is that aging is defined by Programmed Epigenomic Changes. The age-related changes include an accumulation of damage affecting DNA, proteins, membranes, and organelles and decline in maintenance and repair on the cell level. On the more macroscopic level these changes show up as the usual indicators of aging including decline in organ function, decline in hormone levels, loss of muscle mass and grey hair. To be more precise, aging is not a program in itself but is a consequence of the totality of biochemical programs that operate in an individual over that individual’s lifespan. Those programs are species-specific and define typical average and maximum lifespan for each species. We don’t yet understand what the main programs are for most species including humans. We are starting to understand some of the subroutines and sub-subroutines, however, mechanisms that regulate cell cycles and the roles of key genes and proteins. For example we know there is a family of proteins called Sirtuins that are closely implicated in aging processes. One pathway, known as the calorie-restriction pathway, operates in a wide variety of organisms and in humans involves the sirtuin protein SIR1. Activation of that pathway appears to make up to 30% life extension available across a variety of species.
The Telomere Shortening theory of aging fits in neatly as a component of the Aging as Programmed Epigenomic Changes theory. Other aging programs could involve age-related increases in NF-kappaB and P16. These and associated increases could lead to age-related Decline In Adult Stem Cell Differentiation, another of the theories of aging. The basis for regeneration of aging tissues is provided by adult stem cells. P16 protects against cancers but induces premature senescence in progenitor cells. Progenitor stem cells play important roles in the maintenance of homeostasis in cardiac and other tissues and organ maintenance and repair after injury.
Oxidative Damage fits in as an important driver of aging and is implicated in the processes of several of the other theories of aging. We know for example that Oxidative Damage leads to Telomere Shortening. It is also a major cause of Cell DNA Damage which in turn can lead to Susceptibility to Cancers. Mitochondrial Damage can be brought about through Oxidative Damage or via signaling pathways conditioned by Programmed Epigenomic Changes. In turn, faulty mitochondrial functioning can lead to a number of metabolic disease conditions and faulty mitochondrial signaling can lead to errors in apoptosis and a multiplicity of disease susceptibilities including Susceptibility to Cancers and Susceptibility to Cardiovascular Disease. Just about every cellular process involves the operation of multiple feedback loops. Whether and how much exposure to oxidative conditions actually leads to aging depends on numerous factors such as the availability of antioxidant defenses. Natural antioxidant defenses decline with aging, another aspect of the epigenomic aging program driven by changes in the chromatin of cells which accumulate with age.
The feedback loops between many body systems are so tightly interrelated that it is difficult to say where one theory leaves off and and another one starts. Considering the Decline in hormone levels and the Neurological degeneration theories, for example, it has long been known that “the neuroendocrine and immune systems are intimately integrated into one system that provides a complex homeostatic network(ref).” And auto-immune diseases like lupus erythematosus and rheumatoid arthritis can involve Chronic inflammation.
A simplified example of how seven of the aging theories link together is that Oxidative Damage activates NF-kappaB (the Programmed Epigenomic Changes theory of aging) resulting in expression of pro-inflammatory genes leading to a chronic inflammatory response. The inflammatory response is a mechanism in turn deeply implicated in Susceptibility to Cancers and Susceptibility to Cardiovascular Diseases, and Neurological Degeneration. Nothing is really simple, however. Whether a cancer cell is subject to apoptosis or proliferates is dependent on other epigenomic considerations such as the availability of a strong P16 or P53 defense.
Chronic Inflammation is a part of an aging-related program that can be triggered by numerous stimuli, is generally mediated by a gene activation sequence triggered by overexpression of NF-kappaB and related factors, and is an entry portal to several other of the aging related conditions including Tissue Glycation, Susceptibility to Cardiovascular Disease, Neurological Degeneration, and Susceptibility to Cancers. Telomere Shortening and Damage leads in time to cell senescence, apoptosis and mutations which in turn generate a number of the epigenomic-mediated aging conditions including Immune System Deterioriation, Susceptibility To Cancers, Susceptibility to Cardiovascular Disease, Neurological Degeneration, and atrophy of hormone-producing organs leading to Declines in Hormone Levels. The later is an example of the feedback between cell-level and organ-level functioning showing how damage on one level can cause damage on the other level as well.
The pathways affecting aging are complex and multiply interconnected. And gene expression as well as activation of factors like NF-kappaB are themselves dependent on the state of the epigenome and are therefore functions of age.
During chronic diseases there is generally a decline in the functioning of adult stem cells, cells essential for organ repair and regeneration. The same happens in the process of aging. The survival of adult stem cells and their ability to differentiate depends on the presence of growth regulatory signals and NF-kappaB plays an important epigenomic role in this process. Also, Telomere Shortening and Damage in adult stem cells may be a major cause of age-related Decline In Adult Stem Cell Differentiation.
Telomere Shortening and Damage itself, on the other hand, appears to be not inexorable because long-term population studies show that for some individuals telomeres actually get longer over substantial time periods. Telomere shortening may be caused by stress and oxidation, but may be mitigated by effective expression of telomerase which in turn requires the availability of telomerase binding proteins which is dependent on the states of histone acetylation of the DNA binding sites for these protein – e.g. on their epigenomic states. Another of the Sirtuins, SIR6, appears to play a key role in maintaining telomeric integrity by preventing telomere looping and other damaging conditions, another link between the Programmed Epigenomic Changes and the Telomere Shortening and Damage theories of aging.
Stem Cell Differentiation is very different than the Telomere Shortening. And these two theories seem to be different than the 2nd theory Cell DNA Damage. However, a number of recent studies show a growing web of relationships among these theories. For example, telomeric dysfunction may be at the heart of the decreasing capability of stem and progenitor cells to replicate and renew tissues with increasing age. The studies have looked at telomere shortening in hematopoietic stem cells (HSC), mesenchymal progenitor cells, osteoblasts and neural progenitor cells. One study suggests that proteins secreted from telomere-dysfunctional bone-marrow cells may provide accurate biomarkers of aging. As usual when it comes to aging, there are wheels within wheels. Among the many cellular proteins that influence telomere structure, function and enlongation are the telomerase binding factors TRF1 and TRF2 and less-directly shelterin-complex, PinX, Apollo and tankyrase. TRF2seems to play a key role in the differentiation of neural stem cells as well as in cancer proliferation. In a closely related front, telomerase expression and TRF2 seem to play key roles in maintenance of DNA repair mechanisms in neural cells and stem cells.
Lipofuscin Accumulation is driven by a history of metabolic processes dependent on the mitochondria, facilitated by oxidative stress and conditioned by the availability of substances which pump lipofuscin out of cells which depend on the epigenomic states of the cells. Declines in Hormone Levels may be the result of some kind of epigenomic program as well as a consequence of hormone-producing organ deterioration. In fact hormones are intermediary epigenomic factors because they themselves lead to changes in gene expression that affect the production of other hormones as well as disease susceptibilities and other markers of aging.
Additional discussions of how the theories of aging link to one another are provided in the Note New evidence linking the aging theories and Linking up the theories of aging. The Note describes crossover links among at least four of the theories: Programmed genetic changes, Oxidative damage to tissues, Chronic inflammation, and Telomere shortening and damage. The blog entry describes a link between the Telomere shortening and damage, the Programmed epigenomic changes, the Susceptibility to cancers and the Decline in adult stem cell differentiation theories.
The above is just a starting sampler of known links among the theories of aging. It seems that research revealing a new link or shedding new light on existing ones is reported almost every week. As this happens, we are getting closer to understanding aging and what can be done about it. While we are not there yet we are getting closer to a unified theory of aging. Also it is already clear how an anti-aging firewall intervention intended to address aging according to one theory, e.g., taking astragaloside IV as a supplement to activate telomerase expression, addresses aging according to several other of the theories as well. The same is essentially true of most of the supplements in the combined firewall, they being antioxidants and/or inhibitors of NF-kappaB.”