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Compromised autophagy is observed in numerous ageing conditions including neurodegeneration and immunosenescence [8, 9]. Importantly activation of autophagy can increase mouse lifespan [10], and even improve immune response to vaccination in older humans by overcoming immunosenescence [11]. While originally considered under hallmark ‘altered proteostasis’, autophagy regulates a number of other hallmarks of ageing such as DNA repair and nutrient sensing/metabolism [12], and hence it was proposed to be categorised as an integrative hallmark. |
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Dysregulation of RNA processing has been noted in human ageing population studies [13] while interventions that appear to reverse senescent phenotypes act at least in part by restoring youthful patterns of splicing factor expression [14]. Similarly, alternative polyadenylation of mRNAs, already known to contribute to cancer [15] is altered with ageing and may contribute to senescence [16]. Such changes in RNA processing add an additional layer of gene expression control over those of genome integrity, transcriptional efficacy and epigenetic regulation that are already known to change during biological ageing. |
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Microbiome disturbances: recent advances in next generation sequencing technologies have allowed the identification of notable changes in the gut microbiome with age [17], pointing in particular to shifts in microbial populations and loss of species diversity. Together with age-associated loss of structural integrity of the gut and other barriers (e.g. blood brain barrier), this shift in microbial populations can drive inflammation. |
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Altered mechanical properties applies both to cells and to the extracellular milieu. For example, fibroblast senescence is accompanied by a major change from a mobilizable pool of actin that can be readily polymerised and depolymerised during cell motility, to stable stress fibres of f-actin anchored through focal adhesions to the substrate [18], which is particularly marked in cells from patients with premature ageing syndromes [19] and which is likely to impact on cell motility and cell-cell communication. Motility changes are of major relevance in innate immune system ageing, where neutrophils from old donors cause significant tissue damage on migration to sites of inflammatory signalling; modification of the small G protein signalling pathways that regulate such cytoskeletal motility through treatment with statins greatly improves older neutrophil action in vitro and results in highly significant increases in 6 month mortality follow up from older adults admitted to the ICU with pneumonia [20]. The nucleoskeleton is also altered during ageing, with the nuclear lamina becoming destabilised, with concomitant extrusion of chromatin into the cytoplasm as CCFs which trigger the SASP in senescence [21]. Importantly, the nuclear lamina is highly defective in Hutchison-Gilford progeria [22] and clinical trials of farnesyl transferase inhibitors that restore NE integrity increase patient lifespan [23]. Finally, extracellular matrix also changes with ageing, which greatly alters cell behaviour [24]. Increased rigidity and loss of elasticity, for example arising through glycation cross-links between collagen molecules, can lead to multiple age-related disease states such as hypertension with concomitant kidney and neurological defects – such cross-linking may contribute to the accelerated ageing seen in patients with diabetes [25]. The field of mechanobiology and its intersection with ageing is thus very promising in terms of ‘rejuvenation’. |
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Inflammation: Inflammageing, age-dependent chronic inflammation, is implicated in a wide range of age-related diseases [26]. Ageing correlates with high, levels of inflammatory mediators in the blood, such as IL-1, IL-6, C-reactive protein, IFNα, and several others [27]. Originally inflammation was considered part of the hallmark 'altered intercellular communication', however it could be considered on its own merit, due to its large contribution to the ageing process and its cross-play with other hallmarks such as cellular senescence and the newly proposed gut microbiota [26, 28]. |
