“ Our findings support a model of liver injury that occurs independently of obesity, steatosis, or insulin resistance .”
BUFFALO, NY — September 16, 2026 — A new research paper was published in Volume 18 of Aging on August 28, 2026, titled “ Human-relevant Ptpn6 mutation alters immune and hepatic functions during aging .”
The study examines how a mutation affecting the immune and metabolic regulator SHP-1 reshapes liver function during aging, revealing that improved glucose metabolism can coexist with immune-cell accumulation and liver fibrosis.
The research was led by first author Beisy Laborit Labrada from the Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), Université Laval, Québec, Canada . André Marette, from CRIUCPQ and the Department of Medicine at Université Laval , is the corresponding author.
SHP-1, encoded by the PTPN6 gene, is a protein tyrosine phosphatase that helps regulate both immune responses and metabolic signaling. In immune cells, it generally restrains signaling pathways that control cellular activation, while in metabolic tissues it acts as a negative regulator of insulin signaling. This dual function places SHP-1 at an important intersection between immunity and metabolism, two systems that undergo substantial changes during aging.
The study centered on a rare PTPN6 Ala455Thr variant originally identified in a French-Canadian family with early-onset severe emphysema. The human mutation moderately reduces SHP-1 phosphatase activity. To investigate its longer-term effects, the researchers used mice carrying the corresponding Ptpn6 Ala457Thr mutation and compared young adult mice at 5.6 months with older animals at 16–19 months. Unlike more severe SHP-1-deficient mouse models, these animals have lifespans comparable to wild-type mice, allowing the consequences of partial SHP-1 dysfunction to be examined across aging.
The effects were strongly age-dependent. Young adult mutant mice showed metabolic profiles broadly comparable to their wild-type counterparts. In older animals, however, the mutation was associated with lower body and adipose tissue weights, lower fasting glucose, improved glucose tolerance and enhanced hepatic insulin signaling. These findings indicated that the phenotype required time to develop and pointed to the liver as a major metabolic organ affected by partial SHP-1 dysfunction during aging.
Despite these apparently favorable metabolic effects, the livers of older mutant mice showed a very different picture. Histological analysis revealed abnormal immune-cell accumulation and increased collagen deposition and fibrosis, even as liver triglyceride content and steatosis were reduced. The findings therefore separate liver inflammation and fibrosis from the insulin resistance, obesity and lipid accumulation with which they are often associated.
RNA sequencing and immune-cell analyses provided further insight into this phenotype. The researchers identified substantial enrichment of B lymphocytes and macrophages in the livers of aged mutant mice. B220 staining also revealed tertiary lymphoid structures, organized immune-cell aggregates that can develop in non-lymphoid tissues during chronic inflammation, disease and aging. By contrast, most other immune-cell populations showed relatively little change.
The researchers also identified increased IL-6–JAK–STAT3 signaling as a potential mechanism linking altered immune regulation with liver fibrosis. STAT3 phosphorylation was increased in whole liver tissue from older mutant mice. However, primary hepatocytes isolated from these animals did not show the same change, suggesting that increased STAT3 activation primarily reflected infiltrating immune cells rather than an intrinsic alteration within hepatocytes. Consistently, aged mice with hepatocyte-specific SHP-1 deletion did not reproduce the abnormal B-cell and macrophage infiltration.
“ Thus, aging may act as a permissive factor that unmasks the pathological consequences of partial SHP-1 dysfunction, facilitating the accumulation of B cells and macrophage subsets, as well as the progression towards fibrosis. ”
One of the study’s most notable findings is the apparent disconnect between inflammatory liver remodeling and metabolic control. Older mutant mice developed increased hepatic B-cell and macrophage infiltration and fibrosis while simultaneously showing improved glucose metabolism and liver insulin action. The authors suggest that increased IL-10 production in peripheral tissues, including visceral adipose tissue and spleen, may contribute to preserved metabolic homeostasis despite progressive liver abnormalities.
These findings illustrate how partial SHP-1 dysfunction can produce different effects depending on cell and tissue context. Reduced SHP-1 activity can enhance inflammatory responses in immune cells while relieving inhibitory control over insulin signaling in insulin-responsive tissues. The coexistence of these processes suggests that inflammation and improved insulin signaling can develop as distinct consequences of the same genetic alteration during aging rather than moving together in a simple relationship.
The study also has important limitations. The principal aging experiments were performed in male mice, so the researchers emphasize that possible sex-specific immunometabolic and fibrotic effects remain unknown. Although the mutation corresponds to a human variant, the hepatic and metabolic findings were demonstrated in mice and should not be assumed to occur in people carrying the PTPN6 Ala455Thr variant. Additional studies are also needed to establish the specific contributions of infiltrating B-cell subsets and macrophages to the liver phenotype.
Overall, the study identifies SHP-1 as an important regulator of the interaction between immune and metabolic pathways during aging. Chronic partial SHP-1 dysfunction produced little detectable phenotype in young adult mice but, with age, was associated with substantial immune remodeling and fibrosis in the liver alongside enhanced insulin signaling and glucose control. The findings provide a model for understanding how aging can expose the consequences of mild genetic dysfunction and how age-related liver fibrosis may develop independently of traditional metabolic risk factors.
Paper DOI : https://doi.org/10.18632/aging.206413
Corresponding author: André Marette – andre.marette@criucpq.ulaval.ca
Keywords: SHP-1/Ptpn6, B cell, macrophage, aging, Ptpn6 Ala457Thr
Click here to sign up for free Altmetric alerts about this article.
______
To learn more about the journal, please visit www.Aging-US.com and connect with us on social media:
Click here to subscribe to Aging publication updates.
For media inquiries, please contact media@impactjournals.com .
Aging-US
News article
Animals
Human-relevant Ptpn6 mutation alters immune and hepatic functions during aging
28-Aug-2026
The authors declare that they have no conflicts of interest.