Their findings suggest that with aging, collagen deposition exceeds collagen breakdown, and that preventive treatments should shift from drugs that inhibit collagen synthesis, which also interfere with the normal response to tissue injury, to those that promote the resolution of fibrosis.
"We have been working for more than 10 years on the prediction of chronic diseases, like kidney or cardiovascular diseases, and we know that fibrotic processes are the major reason for the progression of these diseases," Dr. Harald Mischak of Mosaiques-Diagnostics in Hannover, Germany told Reuters Health by email on behalf of the authors.
"Fibrosis is thought to be the result of, among other (factors), increased collagen synthesis," he said. "However, our data indicate that not synthesis, but rather an attenuation of physiological collagen turnover and degradation may be responsible for fibrosis. If this hypothesis is correct, then this would have major implications for treatment."
As reported in The Lancet Healthy Longevity, the authors analyzed data from participants in The Flemish Study on Environment, Genes and Health Outcomes (FLEMENGHO), done in northern Belgium from 1985 to 2019, and invited participants to follow-up examinations in 2005-10 and 2009-13.
Participants who took part in both follow-up visits constituted the derivation dataset, which included their 2005-10 data, and the time-shifted internal validation dataset, which included their 2009-13 data.
Those who had only 2005-10 data constituted the synchronous internal validation dataset.
The UPP was further validated in patients with diabetes, COVID-19, or chronic kidney disease (CKD). The Reactome and Kyoto Encyclopedia of Genes and Genomes databases were used to explore molecular pathways.
A total of 778 individuals (mean age, 51; 51% women) had a follow-up examination from 2005-2010 (derivation dataset), of whom 559 had a further follow-up from 2009- 2013 (time-shifted internal validation dataset); 219 were examined only once (synchronous internal validation dataset).
After correction for multiple testing and multivariable adjustment, chronological age was associated with 210 sequenced peptides mainly showing downregulation of collagen fragments. The trained model relating chronological age to UPP included 54 peptides from 17 proteins.
The UPP-age prediction model explained 76.3% of chronological age in the derivation dataset, 54.4% in the time-shifted validation dataset, and 65.3% in the synchronous internal validation dataset.
Compared with chronological age, the predicted UPP-age was greater in patients with diabetes (chronological age 50.8 vs. UPP-age 56.9 years), COVID-19 (53.2 vs. 58.5), and CKD (54.6 vs. 62.3).
Dr. Mischak noted, "The only two drugs that have been approved in several countries so far for the treatment of fibrotic disease are nintedanib and pirfenidone, both for patients with idiopathic pulmonary fibrosis. However, it is unknown if these drugs could affect fibrosis associated with aging; this would have to be investigated in a proper clinical study."
Meanwhile, he added, "Know your urinary proteome to plan your roadmap to healthy aging! Each of us can start changing our lifestyle to prevent fibrotic processes: Stop smoking, reduce body fat, reduce stress levels, be more (physically active), etc.
Dr. Joost-Peter Schanstra, Director of Research and Group Leader at the Renal Fibrosis Lab at INSERM, told Reuters Health by email that he agrees with the study findings "and fully agree to shift the research focus to the degradation of the ECM, and to detect this early. We are currently writing a French preclinical project towards developing such an approach."
SOURCE: https://bit.ly/3pkt7S2 Lancet Healthy Longevity, online October 14, 2021.
By Marilynn Larkin
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