Growth in the number of senescent cells that linger in tissues is one of the root causes of aging. In this context, the open access paper noted here illustrates a couple of points that are worth bearing in mind while thinking about the biochemistry of aging, the first of which is that aging is a feedback loop of damage. Cell and tissue damage generates more cell and tissue damage, which is why aging accelerates as it progresses. The same rough structure of events is found in the age-related failure of any complex machinery.
The second point is that many of the mechanisms and relationships established in past research now make a lot more sense in the context of senescent cells as a driver of aging. The relationship partially outlined by the authors of this paper is an unusually compact feedback loop: senescent cells contribute to kidney dysfunction, for example through a disruption of normal tissue maintenance that produces fibrosis. Scar tissue forms in place of necessary small-scale structures, and in organs like the kidneys those structures are needed for normal function. Kidney dysfunction can in turn lead to stressful metabolic states such as hyperphosphatemia that encourage more cells to become senescent - and not just in the kidneys. It is a downward spiral, one repeated in many different ways through the aged body.
Hyperphosphatemia is a pathological condition related to chronic kidney disease (CKD) and more recently found on premature aging syndromes. High concentration of serum phosphate has profound effects on vascular cell behavior and on vascular function, and has been associated with cardiovascular disease in patients with CKD. Phosphate toxicity has been related with many other organ dysfunctions. However, less is known about the effect of hyperphosphatemia on vascular endothelial cells. A few works have described that a high extracellular phosphate level induces endothelial dysfunction via various mechanisms, including a decline in nitric oxide (NO) release due to oxidative stress.
Endothelium exerts multiple functions to preserve vascular homeostasis. Vasoactive endothelial factors such as NO or ET-1 are involved in this regulation. An unbalanced production of these bioactive mediators results in endothelial dysfunction, a critical event in the development of renal and cardiovascular damage in some diseases such as diabetes, hypertension, or atherosclerosis. On the other hand, vascular dysfunction has been related to endothelial senescence. Cellular senescence is considered one of the hallmarks of aging, and the presence of senescent cells in the tissue can induce or increase some pathologies. Senescent cells are not able to proliferate and present some morphological and biochemical changes, such as increased senescent activity of β-galactosidase (SA-β-GAL) and increased expression of cell cycle inhibitors such as p16 or p53 tumor suppressor genes.
Senescence can be promoted by the replicative life of cells, due to the progressive telomere shortening or prematurely in response to stressful stimuli, which result in DNA damage or oncogene activation. Recent studies from our group have demonstrated that hyperphosphatemia could be one of these stressful stimuli, as it induced cellular senescence in human aortic smooth muscle cells through the activation of IGF-1 receptor and integrin-linked kinase overexpression. The present work shows, for the first time, the key role of ET-1 in the senescence process induced by hyperphosphatemia. We show that a high extracellular phosphate concentration up-regulates the synthesis of ET-1 in endothelial cells, inducing cellular senescence through the modulation of ECE-1 via oxidative stress and AP-1 activation. Thus the hyperphosphatemia related to aging or aged diseases could increase senescent cells, which could be involved in the development of other pathologies.