IMPACT OF NEPHRON NUMBER ON BIOLOGICAL AGE: EXPLORING A POTENTIAL BIOMARKER OF AGEING

A progressive loss of nephrons accompanies ageing. Physiological nephron loss occurs with advancing age, but in chronic kidney disease (CKD) this process is anticipated. We speculate that this leads to an earlier and steeper decline in biological functions. The kidney may act as a “digital clock” of ageing, in which the progressive reduction in nephron number closely parallels biological age. This concept is supported by evidence of premature ageing phenotypes in patients with CKD and in those undergoing dialysis. The study aims to show that in CKD patients, biological age exceeds their chronological age. We also show that the phenomenon of reverse epidemiology (lower mortality in obese hemodialysis patients) can be explained by a faster ageing process. Identifying nephron number as a biomarker of biological age may provide new insights into ageing mechanisms and support targeted interventions, including physical exercise, to mitigate functional decline. Ultimately, this approach could offer innovative strategies to improve prognosis and quality of life in CKD patients.

A retrospective observational study was conducted on 50 patients over 18 years of age with CKD at different stages. Oncological patients, diabetic nephropathy and septic patients were excluded. Multiple linear regression models were performed to explore associations between biological age, serum creatinine, estimated glomerular filtration rate (eGFR), and sex. Biological age was estimated using the PhenoAge algorithm, a validated biomarker of ageing based on clinical and biochemical parameters. Year loss was defined as the difference between chronological and biological age. Nephron number was indirectly estimated from patients’ eGFR values using a formula derived from Yusuke Fukao et al data (2025; see Figure 1A). BMI vs mortality curves (Reverse epidemiology) in hemodialysis patients were obtained with a metanalysis based on literature data.

A significant inverse relationship emerged between nephron number and years lost (chronological age – biological age; r = −0.84, p < 0.001; figure 1B), indicating that individuals with higher nephron endowment exhibit slower biological aging. In the multiple regression model, there was no significant gender effect. Specifically, biological age increased by 5 years over the chronological age for every 100,000 nephrons lost. 

In the general population, the value of BMI associated with the lowest mortality is 18-25 kg/m2 in subjects younger than 65 years (Figure 1C). The minimum of mortality value moves for values of BMI of 25-30 Kg/m2 in the group older than 65 years. Mortality in HD patients is significantly higher than in the general population. Furthermore, in these patients, we can witness the phenomenon of reverse epidemiology as the optimal BMI associated with a more prolonged survival increases with increasing age. The BMI-mortality curve of HD patients is shifted to the right and up with respect to the general population. We further show that the shift towards the right can be explained by an increase of the biological age of HD patients, so that they behave as if they have an average of 10 years more than their chronological age.

Aging involves the whole organism and may be regulated by an integrated biological clock in which the kidney plays a key role (Fig 1D). Understanding this mechanism could guide strategies to slow physiological decline and extend lifespan.