Telomere dysfunction in chronic liver disease: The link from aging

Penrice, Daniel D.; Jalan‐Sakrikar, Nidhi; Jurk, Diana; Passos, João F.; Simonetto, Douglas A.

doi:10.1097/hep.0000000000000426

Cited by 4 publications

(3 citation statements)

References 150 publications

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“…The loss of TRMs in these specified niches is likely to predispose the tissue to increased infiltrates, fibrosis and pathogen susceptibility 36,51,52,72,73 . Moreover, the loss of interaction with stellate cells in STING -/livers may have another outcome, liver fibrosis is a common feature of aging livers and considered pathological 72,[74][75][76][77][78] . However, fibrosis may have the inadvertent benefit of maintaining structural integrity of the tissue architecture.…”

Section: Discussionmentioning

confidence: 99%

STING promotes homeostatic maintenance of tissues and confers longevity with aging

Hopkins,

Sulka,

Sawden

et al. 2024

Preprint

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SUMMARYLocal immune processes within aging tissues are a significant driver of aging associated dysfunction, but tissue-autonomous pathways and cell types that modulate these responses remain poorly characterized. The cytosolic DNA sensing pathway, acting through cyclic GMP-AMP synthase (cGAS) and Stimulator of Interferon Genes (STING), is broadly expressed in tissues, and is poised to regulate local type I interferon (IFN-I)-dependent and independent inflammatory processes within tissues. Recent studies suggest that the cGAS/STING pathway may drive pathology in variousin vitroandin vivomodels of accelerated aging. To date, however, the role of the cGAS/STING pathway in physiological aging processes, in the absence of genetic drivers, has remained unexplored. This remains a relevant gap, as STING is ubiquitously expressed, implicated in multitudinous disorders, and loss of function polymorphisms of STING are highly prevalent in the human population (>50%). Here we reveal that, during physiological aging, STING-deficiency leads to a significant shortening of murine lifespan, increased pro-inflammatory serum cytokines and tissue infiltrates, as well as salient changes in histological composition and organization. We note that aging hearts, livers, and kidneys express distinct subsets of inflammatory, interferon-stimulated gene (ISG), and senescence genes, collectively comprising an immunefingerprintfor each tissue. These distinctive patterns are largely imprinted by tissue-specific stromal and myeloid cells. Using cellular interaction network analyses, immunofluorescence, and histopathology data, we show that these immune fingerprints shape the tissue architecture and the landscape of cell-cell interactions in aging tissues. These age-associated immune fingerprints are grossly dysregulated with STING-deficiency, with key genes that define aging STING- sufficient tissues greatly diminished in the absence of STING. Changes in immune signatures are concomitant with a restructuring of the stromal and myeloid fractions, whereby cell:cell interactions are grossly altered and resulting in disorganization of tissue architecture in STING-deficient organs. This altered homeostasis in aging STING-deficient tissues is associated with a cross-tissue loss of homeostatic tissue-resident macrophage (TRM) populations in these tissues.Ex vivoanalyses reveal that basal STING- signaling limits the susceptibility of TRMs to death-inducing stimuli and determines theirin situlocalization in tissue niches, thereby promoting tissue homeostasis. Collectively, these data upend the paradigm that cGAS/STING signaling is primarily pathological in aging and instead indicate that basal STING signaling sustains tissue function and supports organismal longevity. Critically, our study urges caution in the indiscriminate targeting of these pathways, which may result in unpredictable and pathological consequences for health during aging.HIGHLIGHTSAging tissues are associated with tissue-autonomousimmunefingerprints, primarily driven by interactions of tissue stromal and myeloid populations.STING shapes these immune fingerprints of aging tissues in unexpected ways.Loss of STING alters the location, numbers, and viability of tissue resident macrophages.STING signaling is critical for longer lifespans and maintenance of tissue architecture.

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Section: Discussionmentioning

confidence: 99%

STING promotes homeostatic maintenance of tissues and confers longevity with aging

Hopkins,

Sulka,

Sawden

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Meanwhile, testing for TBD, either through Flow-FISH or genetic screening, in patients with unexplained liver abnormalities may become a standard practice which will help identify those at risk of TBD. [6] Furthermore, recognition of known TRG mutations will allow for appropriate screening in first-degree relatives, as indicated.…”

mentioning

confidence: 99%

“…This study, among others, suggests that androgen therapy may be a promising avenue for addressing telomere shortening in patients with TBD, but whether they significantly change the course of liver disease remains to be seen. Meanwhile, testing for TBD, either through Flow-FISH or genetic screening, in patients with unexplained liver abnormalities may become a standard practice which will help identify those at risk of TBD 6 . Furthermore, recognition of known TRG mutations will allow for appropriate screening in first-degree relatives, as indicated.…”

mentioning

confidence: 99%