bims-minfam 2024-02-11 papers

Issue of 2024–02–11
five papers selected by
Ayesh Seneviratne, Western University

NEJM Evid. 2023 May;2(5): EVIDe2300053

How Great Is the Threat of Clonal Hematopoiesis? Let This New Risk Score Be Your Guide.

The recent expanding compendium of sequencing analysis has offered insight into the pathobiology of myeloid neoplasms. This molecular evidence of clonal hematopoiesis provides information to allow earlier identification of predisposition states to myeloid neoplasms, such as clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of unknown significance (CCUS). The ability to risk-stratify cases of clonal hematopoiesis that may evolve to frank myeloid neoplasms is essential to manage expectations for patients and providers alike.

DOI: https://doi.org/10.1056/EVIDe2300053

Nat Cell Biol. 2024 Feb 08.

Mitochondrial DNA replication stress triggers a pro-inflammatory endosomal pathway of nucleoid disposal.

Laura E Newman, Sammy Weiser Novak, Gladys R Rojas, Nimesha Tadepalle, Cara R Schiavon, Danielle A Grotjahn, Christina G Towers, Marie-Ève Tremblay, Matthew P Donnelly, Sagnika Ghosh, Michaela Medina, Sienna Rocha, Ricardo Rodriguez-Enriquez, Joshua A Chevez, Ian Lemersal, Uri Manor, Gerald S Shadel.

Mitochondrial DNA (mtDNA) encodes essential subunits of the oxidative phosphorylation system, but is also a major damage-associated molecular pattern (DAMP) that engages innate immune sensors when released into the cytoplasm, outside of cells or into circulation. As a DAMP, mtDNA not only contributes to anti-viral resistance, but also causes pathogenic inflammation in many disease contexts. Cells experiencing mtDNA stress caused by depletion of the mtDNA-packaging protein, transcription factor A, mitochondrial (TFAM) or during herpes simplex virus-1 infection exhibit elongated mitochondria, enlargement of nucleoids (mtDNA-protein complexes) and activation of cGAS-STING innate immune signalling via mtDNA released into the cytoplasm. However, the relationship among aberrant mitochondria and nucleoid dynamics, mtDNA release and cGAS-STING activation remains unclear. Here we show that, under a variety of mtDNA replication stress conditions and during herpes simplex virus-1 infection, enlarged nucleoids that remain bound to TFAM exit mitochondria. Enlarged nucleoids arise from mtDNA experiencing replication stress, which causes nucleoid clustering via a block in mitochondrial fission at a stage when endoplasmic reticulum actin polymerization would normally commence, defining a fission checkpoint that ensures mtDNA has completed replication and is competent for segregation into daughter mitochondria. Chronic engagement of this checkpoint results in enlarged nucleoids trafficking into early and then late endosomes for disposal. Endosomal rupture during transit through this endosomal pathway ultimately causes mtDNA-mediated cGAS-STING activation. Thus, we propose that replication-incompetent nucleoids are selectively eliminated by an adaptive mitochondria-endosomal quality control pathway that is prone to innate immune system activation, which might represent a therapeutic target to prevent mtDNA-mediated inflammation during viral infection and other pathogenic states.

DOI: https://doi.org/10.1038/s41556-023-01343-1

Int J Mol Sci. 2024 Feb 01. pii: 1792. [Epub ahead of print]25(3):

Senotherapeutics to Counteract Senescent Cells Are Prominent Topics in the Context of Anti-Ageing Strategies.

Anna Calabrò, Giulia Accardi, Anna Aiello, Calogero Caruso, Damiano Galimberti, Giuseppina Candore.

Cellular senescence is implicated in ageing and associated with a broad spectrum of age-related diseases. Importantly, a cell can initiate the senescence program irrespective of the organism's age. Various stress signals, including those defined as ageing hallmarks and alterations leading to cancer development, oncogene activation, or loss of cancer-suppressive functions, can trigger cellular senescence. The primary outcome of these alterations is the activation of nuclear factor (NF)-κB, thereby inducing the senescence-associated secretory phenotype (SASP). Proinflammatory cytokines and chemokines, components of this phenotype, contribute to chronic systemic sterile inflammation, commonly referred to as inflamm-ageing. This inflammation is linked to age-related diseases (ARDs), frailty, and increased mortality in older individuals. Additionally, senescent cells (SCs) accumulate in multiple tissues with age and are believed to underlie the organism functional decline, as demonstrated by models. An escalating effort has been dedicated to identify senotherapeutics that selectively target SCs by inducing apoptosis; these drugs are termed senolytics. Concurrently, small molecules that suppress senescent phenotypes without causing cell death are known as senomorphics. Both natural and synthetic senotherapeutics, along with immunotherapies employing immune cell-mediated clearance of SCs, currently represent the most promising strategies to combat ageing and ARDs. Indeed, it is fascinating to observe that information regarding the immune reaction to SCs indicates that regulation by specific lymphocyte subsets, elevated in the oldest centenarians, plays a role in attaining extreme longevity. Regardless, the application of methods already utilized in cancer treatment, such as CAR cells and monoclonal antibodies, broadens the spectrum of potential approaches to be utilized.

Keywords: ageing; immunosenescence; immunotherapy; senescence; senolytics; senomorphics

DOI: https://doi.org/10.3390/ijms25031792

PLoS One. 2024 ;19(2): e0296014

Frailty before and during austerity: A time series analysis of the English Longitudinal Study of Ageing 2002-2018.

Carys Pugh, Chima Eke, Sohan Seth, Bruce Guthrie, Alan Marshall.

BACKGROUND: Frailty is characterised by a reduced resilience to adversity. In this analysis we examined changes in frailty in people aged 50+ before and during a period of austere public spending in England.
METHODS: Data from the English Longitudinal Study of Ageing 2002-2018 were analysed. Associations between austerity and frailty were examined using (1) Multilevel interrupted times series analysis (ITSA); and (2) Accelerated longitudinal modelling comparing frailty trajectories in people of the same age in 2002 and 2012.
RESULTS: The analysis included 16,410 people (mean age 67 years, 55% women), with mean frailty index score of 0.16. Mean scores in women (0.16) where higher than in men (mean 0.14), and higher in the poorest tertile (mean 0.20) than the richest (mean 0.12). In the ITSA, frailty index scores increased more quickly during austerity than before, with the additional increase in frailty 2012-2018 being similar in magnitude to the difference in mean frailty score between people aged 65-69 and 70-74 years. Steeper increases in frailty after 2012 were experienced across the wealth-spectrum and in both sexes but were greater in the very oldest (80+). In the accelerated longitudinal analysis, frailty was lower in 2012 than 2002, but increased more rapidly in the 2012 cohort compared to the 2002 cohort; markedly so in people aged 80+.
CONCLUSION: The period of austerity politics was associated with steeper increases in frailty with age compared to the pre-austerity period, consistent with previously observed increases in mortality.

DOI: https://doi.org/10.1371/journal.pone.0296014