Chronic kidney disease (CKD) is a particular unpleasant condition, not least because it accelerates many of the other manifestations of aging, but also because there is comparatively little that can be done to treat it at this time. There are lines of work based around suppressing fibrosis characteristic of aged, damaged kidneys, and also the potential use of stem cell therapies to regenerate healthy kidney tissue, but practical implementations are yet to emerge. Since a little less than 10-20% of the adult population in developed nations suffers from chronic kidney disease, depending on where you want to drawn the line, progress on the path to treatments has the potential to help a large number of patients.
One of the signs of failing kidney function is uremia, the increased presence of metabolic products such as urea in the bloodstream. It shows that the kidneys are not filtering as well as they should, and as levels of these unwanted products grow they are accompanied by a very broad range of damaging and increasingly serious consequences. Many of these consequences look a lot like the general progression of aging from the outside: increased frailty on many counts, and increased risk of suffering other age-related conditions.
In this open access review paper the authors seek to draw comparisons between the biochemistry of aged people without chronic kidney disease and younger people suffering the condition. There are numerous similarities, but is this a case in which those similarities are a learning opportunity? This is a question perhaps worth thinking about in the context of type 2 diabetes, a condition that can also be thought of as accelerating certain aspects of aging, and has for some time been used in animal studies as a model substitute for aging.
Observation alone suggests that patients with end stage kidney disease (ESKD) are biologically older than their unaffected peers. As a group, ESKD patients have a morbidity and mortality profile similar to that of the geriatric population, and the pathophysiology of the uremic syndrome has interesting parallels with the aging process. Based on these thoughts it has been posited that kidney failure results in accelerated, pathological aging. Indeed there are striking analogies between the effects of aging and uremia on the structure and function of the heart and vasculature, with similar arterial stiffening-related changes seen in pulse contour, pulse wave velocity, and impedance, and similar structural abnormalities with wall thickening, decreased elastin, and increased collagen content.
Whilst much has already been written about the intriguing similarities that appear to exist between the aging process and CKD, comparatively little work has been undertaken looking at the cellular and molecular hallmarks of aging in the context of the known evidence concerning uremia-induced cellular and molecular pathways.
1) The principle cell death and survival molecular pathways consisting of apoptosis, necroptosis and autophagy are strongly interrelated and crossover at many points. Whilst our current knowledge on how these interacting pathways are controlled and regulated is far from complete there is a growing appreciation of how similar many of the molecular signalling induced by uremia and aging appear to be.
2) Aging and uremia share many important cellular characteristics such as increases in cell senescence, telomere shortening and exhaustion of stem cells. This provides further evidence that supports the contention that uremia can be considered as a form of accelerated aging.
3) The klotho gene was originally identified as being involved in the suppression of aging in transgenic mouse studies. Defective klotho expression resulted in mice having a premature aging phenotype, which had striking similarities to that of CKD patients. The deficiency in klotho seen in uremia and aging might underpin the enhanced cell senescence, apoptosis and stem cell depletion common to both states. Given that tissue klotho expression is greatest in the kidneys a common mechanism is perhaps to be expected.
4) Spontaneous post-translational protein modifications result from the non-enzymatic attachment of reactive molecules to protein functional groups. This process occurs in healthy individuals with aging, but is increased in certain disease states. Alterations to protein structure may result in functional changes, which can be pathogenetic. One of the most widely studied and publicised forms of post-translational protein modification is the formation of advanced glycation end products (AGEs) by the non-enzymatic modification of tissue proteins by physiologic sugars. AGEs accumulate in tissues as a function of increased production (e.g., in diabetes mellitus), decreased renal removal of AGE precursors (e.g., in advanced CKD) and time (as occurs in physiological aging). Increased oxidative stress and AGE generation are known to play a role in the pathophysiology of aging, and both of these events are present in patients with CKD and therefore represent two further potential crossovers between uremia and the aging process.
Based on this evidence it could be posited that the physical resemblance between advanced age and uremia is underpinned by shared cellular and molecular "abnormalities". These observations also reinforce the idea of the "uremic syndrome", in which dysfunctions in multiple body systems arise due to a pervasive defect at a cellular level. Information gathered by research into aging pathways and "anti-aging therapies" might inform interventions to avoid, slow the progression of or even reverse some of the pathological changes seen in uremia. Given that these pathways are seen throughout most tissues and cell types it is also possible that a single intervention might treat several pathologies. However, the aging process remains incompletely understood in healthy individuals, and those pathways that are known are complex and heavily interconnected. Disentangling these in the uremic syndrome, in which multiple co-existing and interdependent metabolic abnormalities arise, will be a challenge.
The point to take away here, I think, is that damage is damage. We suffer age-related degeneration and loss of function because our biology accumulates unrepaired damage of a variety of forms to cells and tissue structure. Clearly some of the detrimental outcomes resulting from damage accumulation reinforce one another to speed up the production of further damage. The whole of aging is an accelerating downward spiral: it isn't a linear process of advancing dysfunction. Frailty and mortality take hold much more rapidly in the later stages.