Aging is characterized by a progressive loss of physiological integrity, leading to generalized cellular, tissue, organ and overall dysfunction with increased vulnerability to disease and ultimately leading to death. This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. But is it chronological aging that creates drivers for these disorders or is it the dysfunctions that cause the deterioration we call “aging”?
It is my contention that “aging” should not be looked at as a chronological attribute but a physiological one. Thus, we should consider our biological age to be determined by the robustness of processes that maintain proper biochemical and physiological homeostatic functionality and that is only approximated by life’s time intervals. It is also becoming more obvious that the relationship between biological aging and disease states is blurred and actually morphs into an aggregate that thus can be addressed as one entity. So, from my perspective, we may (and should) look upon aging as a progressive and ultimately terminal systemic disease state.
This idea need not be looked upon in a maudlin way since if we look at aging as a disease or set of disease conditions we intuitively look at it as being a state that may be amenable to treatments and control and not just palliation.
Recently in the preeminent biological science journal CELL1 there appeared an article that posited the hallmarks of aging and the role each played in the overall systemic dysfunction associated with the aging phenotype. The hallmarks include: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. The authors suggested: that a major challenge is to dissect the interconnectedness between and among the candidate hallmarks and their relative contributions to aging, with the final goal of identifying…targets to improve human health during (chronological) aging, with minimal side effects. There is also implicit in their remarks that if one looks at this overall, one can imagine that if a missing link can be determined and effectively mitigated then aging can be modulated to some degree with a goal of not only increasing lifespan but doing so with improved healthspan.
To be sure, one to several of these hallmarks can be shown to be active in virtually all of the major chronic disease states commonly associated with chronological aging. These include those causing the greatest mortality and morbidity: cardiovascular disease, type II diabetes, cancer, Alzheimer’s disease and other neurological disorders, kidney disease, chronic obstructive pulmonary disease and sarcopenia.
Finding a link among all these hallmarks is not and easy tasks due to the incredible complexity these processes possess. That said, we can look at some very interesting clues pointing to potential culprits within each hallmark mentioned. This does not prove causation but at the very least is a correlate that is worth exploring that even if it turns out to be but one in a myriad of causative factors is a start to be explored.
To be a target worth focusing on the proposed link should be at play within the hallmark process at the most basic levels of physiological or biochemical activity. It should also be identified as an action that if restrained can show the affected processes become revitalized and if enhanced that the processes become increasingly compromised.
A process, reaction if you will, that continues to garner much attention in research circles, even if not in clinical ones, is glycation. Glycation is the damage caused to biological macromolecules such as proteins, lipoproteins and nucleic acids by the reducing sugars or their degradation or precursors and the amino groups of the biopolymeric entities. This glycation reaction changes dramatically their functionality and impacts the processes in which they are key players. Glycation shows itself in virtually all of the chronic disease states mentioned previously. Thus, if we can show it also behaves as a driver in the hallmarks of aging then we may be on to something.
Over the next several posts I will discuss in each one a different hallmark and attempt to show what supports it being included into this lists of aging factors. We will then look at the evidence showing how it causes disease and then investigate glycation’s role in this process and the potential mechanism that corrupts it. Once we conclude the series of posts we will see how one can argue pretty convincingly that to a significant degree glycation can be viewed as a major mode of interconnectedness among these hallmarks of aging and thus to the diseases associated with aging. By doing so it would then seem plausible that ways to limit systemic and targeted glycation pathways should be a means to slow the trajectory of the systemic dysfunction we see as “aging”. This accomplished, maybe, if not defeat, just maybe we can find ways to hold biological aging at bay for a little longer period of time.
- Lopez-Otin, C., et al, The Hallmarks of Aging, 2013, Cell 153, June 6 1194-1217
Nick Pokoluk is a biochemist, Six Sigma Black Belt of Transformational Change Methodology and certified wellness coach. He can be reached at [email protected]
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