Loss of H3K9 trimethylation leads to premature aging.

Aging is the major risk factor for most human diseases and represents a major socio-economical challenge for modern societies. Despite its importance, the process of aging remains poorly understood. Epigenetic dysregulation has been proposed as a key driver of the aging process.

Initiation phase cellular reprogramming ameliorates DNA damage in the ERCC1 mouse model of premature aging.

Unlike aged somatic cells, which exhibit a decline in molecular fidelity and eventually reach a state of replicative senescence, pluripotent stem cells can indefinitely replenish themselves while retaining full homeostatic capacity. The conferment of beneficial-pluripotency related traits via partial cellular reprogramming in vivo partial reprogramming significantly extends lifespan and restores aging phenotypes in mouse models. Although the phases of cellular reprogramming are well characterized, details of the rejuvenation processes are poorly defined.

In vivo reprogramming leads to premature death linked to hepatic and intestinal failure.

The induction of cellular reprogramming via expression of the transcription factors Oct4, Sox2, Klf4 and c-Myc (OSKM) can drive dedifferentiation of somatic cells and ameliorate age-associated phenotypes in multiple tissues and organs. However, the benefits of long-term in vivo reprogramming are limited by detrimental side-effects. Here, using complementary genetic approaches, we demonstrated that continuous induction of the reprogramming factors in vivo leads to hepatic and intestinal dysfunction resulting in decreased body weight and contributing to premature death (within 1 week).

The role of T cells in age-related diseases.

Age-related T cell dysfunction can lead to failure of immune tolerance mechanisms, resulting in aberrant T cell-driven cytokine and cytotoxic responses that ultimately cause tissue damage. In this Review, we discuss the role of T cells in the onset and progression of age-associated conditions, focusing on cardiovascular disorders, metabolic dysfunction, neuroinflammation and defective tissue repair and regeneration. We present different mechanisms by which T cells contribute to inflammageing and might act as modulators of age-associated diseases, including through enhanced pro-inflammatory and cytotoxic activity, defective clearance of senescent cells or regulation of the gut microbiota.

Extracellular Tuning of Mitochondrial Respiration Leads to Aortic Aneurysm.

Background: Marfan syndrome (MFS) is an autosomal dominant disorder of the connective tissue caused by mutations in the (fibrillin-1) gene encoding a large glycoprotein in the extracellular matrix called fibrillin-1. The major complication of this connective disorder is the risk to develop thoracic aortic aneurysm. To date, no effective pharmacologic therapies have been identified for the management of thoracic aortic disease and the only options capable of preventing aneurysm rupture are endovascular repair or open surgery.

Mitochondrial dysfunction defines T cell exhaustion.

When T cells are exposed to continuous antigen stimulation, they become exhausted. Here, we preview findings from Scharping et al. (2021), who have illuminated the molecular mechanism by which the persistent antigen stimulation and severe hypoxic conditions in the intratumoral environment drive T cell exhaustion, losing their cytotoxic function and anticancer effects.

T cells with dysfunctional mitochondria induce multimorbidity and premature senescence.

The effect of immunometabolism on age-associated diseases remains uncertain. In this work, we show that T cells with dysfunctional mitochondria owing to mitochondrial transcription factor A (TFAM) deficiency act as accelerators of senescence. In mice, these cells instigate multiple aging-related features, including metabolic, cognitive, physical, and cardiovascular alterations, which together result in premature death.

The microRNA-29/PGC1α regulatory axis is critical for metabolic control of cardiac function.

Different microRNAs (miRNAs), including miR-29 family, may play a role in the development of heart failure (HF), but the underlying molecular mechanisms in HF pathogenesis remain unclear. We aimed at characterizing mice deficient in miR-29 in order to address the functional relevance of this family of miRNAs in the cardiovascular system and its contribution to heart disease. In this work, we show that mice deficient in miR-29a/b1 develop vascular remodeling and systemic hypertension, as well as HF with preserved ejection fraction (HFpEF) characterized by myocardial fibrosis, diastolic dysfunction, and pulmonary congestion, and die prematurely.

Mitochondrial activity in T cells.

Mitochondria fulfill important and diverse roles during the different stages of T cell adaptive responses. Here we discuss the role of the mitochondria in T cells from the initial steps of activation at the immune synapse to their participation in memory response and T cell exhaustion. Mitochondria are relocated to the immune synapse in order to supply local ATP and to aid calcium signaling.

Role of exosomes in the protection of cellular homeostasis.

Due to their ability to shuttle proteins, lipids and genetic material between distant cells, exosomes promote extensive phenotypic changes in recipient cells, modulating immune responses, cellular migration, cancer metastasis or the spreading of neurotoxic protein aggregates in neurodegenerative diseases. Besides intercellular communication, exosome biogenesis and secretion permit the rapid release of a selective repertoire of compounds, conferring cells with an additional mechanism to fight alterations in protein, lipid or RNA homeostasis during stress or pathological conditions. Here, we review the dual role of the different quality control mechanisms arising from the endolysosomal system and the diverse situations that control the decision between degradation or secretion.