Ageing is the biggest risk factor for cardiovascular disease. Cellular senescence, a process driven in part by telomere shortening, has been implicated in age‐related tissue dysfunction. Here, we address the question of how senescence is induced in rarely dividing/post‐mitotic cardiomyocytes and investigate whether clearance of senescent cells attenuates age‐related cardiac dysfunction. During ageing, human and murine cardiomyocytes acquire a senescent‐like phenotype characterised by persistent DNA damage at telomere regions that can be driven by mitochondrial dysfunction and crucially can occur independently of cell division and telomere length. Length‐independent telomere damage in cardiomyocytes activates the classical senescence‐inducing pathways, p21CIP and p16INK4a, and results in a non‐canonical senescence‐associated secretory phenotype, which is pro‐fibrotic and pro‐hypertrophic. Pharmacological or genetic clearance of senescent cells in mice alleviates detrimental features of cardiac ageing, including myocardial hypertrophy and fibrosis. Our data describe a mechanism by which senescence can occur and contribute to age‐related myocardial dysfunction and in the wider setting to ageing in post‐mitotic tissues.

Plasmacytoid dendritic cells (pDCs) produce large amounts of type I interferons (IFN-␣/␤) in response to viral or endogenous nucleic acids through activation of their endosomal Toll-like receptors (TLR-7and TLR-9). Enhanced TLR-7-mediated IFN-␣ production by pDCs in women, compared with men, has been reported, but whether sex hormones, such as estrogens, are involved in this sex-based difference is unknown. Here we show, in humanized mice, that the TLR-7-mediated response of human pDCs is increased in female host mice relative to male. In a clinical trial, we establish that treatment of postmenopausal women with 17␤-estradiol markedly enhances TLR-7-and TLR-9-dependent production of IFN-␣ by pDCs stimulated by synthetic ligands or by nucleic acid-containing immune complexes. In mice, we found exogenous and endogenous estrogens to promote the TLR-mediated cytokine secretion by pDCs through hematopoietic expression of estrogen receptor (ER) ␣. IntroductionDendritic cells (DCs) are specialized sentinels in the immune system that detect invading pathogens and play a crucial role in orchestrating the immune responses. In response to viral infection, a specialized DC subset, plasmacytoid DCs (pDCs), produces a large amount of type I IFNs (IFN-␣/␤), which are potent anti-viral and immunostimulatory cytokines. 1 pDCs become activated to produce IFN-␣/␤ through Toll-like receptors (TLR-7 and TLR-9) within endosomal compartments that can sense viral nucleic acids. In the context of autoimmune diseases, such as systemic lupus erythematosus (SLE), these TLRs can also be inappropriately activated by self-nucleic acids complexed with autoreactive antibodies, resulting in IFN-␣ production by pDCs. 2 Activation of pDCs by endogenous DNA and RNA has been suggested to play a critical role in promoting and exacerbating SLE. 2-4 SLE patients show increased serum levels of IFN-␣ and overexpression of IFN-␣-regulated genes in blood cells, suggesting a central role for type I IFNs in disease pathogenesis. [5][6][7][8] This is supported by the observation that antinuclear antibody and SLE syndrome can develop during IFN-␣ treatment in patients with nonautoimmune disorders. 9 Likewise, IFN-␣ administration accelerates disease development and enhances disease severity in lupus-prone mouse strains. 10,11 In addition to IFN-␣, TNF-␣ has been shown to be increased in the serum of patients with active SLE disease and correlates with IFN-␣ levels. 12,13 Although pDCs can also produce TNF-␣, it is not clear whether they represent the unique source of this cytokine in SLE. 14 Cumulative evidence supports a role for sex-based differences in the pathogenesis of autoimmune and infectious diseases, which may be the result of sex hormones through their effects on innate and adaptive immunity. 15,16 A strong sex bias is observed in SLE, whose incidence is approximately 9 times higher in women relative to men. 15 Because disease onset is much more frequent in women of childbearing age, it has been hypothesized that sex steroid hormones, such as estro...