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The hallmarks of aging form a catalog of largely better studied changes in cells and tissues considered relevant, and possibly more important, in the onset and development of age-related degeneration and disease. This is not the same thing as a list of causes of aging. A few of the hallmarks mostly likely are or include deeper causes of aging, or close to causes of aging. The hallmarks do overlap with the SENS description of aging as a set of root causes, forms of molecular damage that result from the normal operation of a youthful metabolism. Since the hallmarks of aging are not, and are not intended to be a list of causes of aging, it is always possible to argue for an expansion, particularly since the hallmarks as they stand omit a number of line items that are not as well studied, but still probably important. Equally, once started on an expansion of the hallmarks, where does one stop?
We might ask ourselves: what use is a taxonomy of aging? To my eyes, the best thing that a taxonomy can achieve is to focus research and development efforts in directions that are more likely to produce meaningful gains in health and longevity. It isn’t clear that the hallmarks of aging will achieve that goal, given that the primary issue in the treatment of aging lies in identifying mechanisms that are more rather than less likely to produce large effect sizes when used as a basis for anti-aging therapies. Picking a prevalent aspect of aging is no guarantee of success in this regard. Many quite prominent aspects of aging are far removed from the causes of aging (in the SENS view, at least), and treating them will most likely have little effect on overall health because the underlying causes will continue forward untouched, producing many other problems.
The SENS advocates had the right idea, “let’s just talk about root causes”, which produces a limited list. Whereas if less constrained, to “important things about aging that we’re looking into”, then there is potentially no end to the list, and no guidance as to whether any given hallmark is a good target for intervention. Certainly the hallmarks of aging look more relevant to the field today as the 14 items suggested in the open access conference report below, rather than the original 9 items, but then a decade from now they will look more relevant as 26 items, well on their way to becoming a poor guide to strategy in the treatment of aging as a medical condition.
New hallmarks of ageing: A 2022 Copenhagen ageing meeting summary
The definition of nine cellular and molecular hallmarks of ageing in 2013 provided a contextual framework to guide future ageing research. These hallmarks comprise: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Recently, these hallmarks have been criticized for being insufficient in serving as a causative paradigm of ageing. Importantly though, they have recently been shown to map to age-related diseases. To address this and to explore potential new hallmarks, a research symposium “New Hallmarks of Ageing” was held in Copenhagen (Denmark) on the 22nd of March 2022, focusing on novel findings and the recontextualization of the nine hallmarks of ageing. This included the discussion of new advances and the future of the field of ageing research.
The panel stressed the importance of progress in the field, as ageing is the primary risk factor of many major human diseases. It was highlighted that increasing average lifespan over the last decades is one of the most remarkable human accomplishments, but that this success has led to a different, challenging problem, namely the ever-increasing number of chronically ill patients suffering from age-related diseases, and the resulting toll on individuals and society. Understanding the mechanisms of the ageing process will therefore be pivotal to treat the root cause of multiple age-related diseases. The panellists emphasised that only taking a limited number of defined hallmarks into account might also halt progress on processes relevant to ageing but not currently defined as hallmarks. The panellists thereby discussed the inclusion of new hallmarks to the current list.
1) Compromised autophagy is observed in numerous ageing conditions including neurodegeneration and immunosenescence. Importantly activation of autophagy can increase mouse lifespan, and even improve immune response to vaccination in older humans by overcoming immunosenescence. While originally considered under hallmark ‘altered proteostasis‘, autophagy regulates a number of other hallmarks of ageing such as DNA repair and nutrient sensing/metabolism, and hence it was proposed to be categorised as an integrative hallmark.
2) Dysregulation of RNA processing has been noted in human ageing population studies while interventions that appear to reverse senescent phenotypes act at least in part by restoring youthful patterns of splicing factor expression. Similarly, alternative polyadenylation of mRNAs, already known to contribute to cancer, is altered with ageing and may contribute to senescence. 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.
3) Microbiome disturbances: recent advances in next generation sequencing technologies have allowed the identification of notable changes in the gut microbiome with age, 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.
4) 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, which is particularly marked in cells from patients with premature ageing syndromes and which is likely to impact on cell motility and cell-cell communication. The nucleoskeleton is also altered during ageing, with the nuclear lamina becoming destabilised, with concomitant extrusion of chromatin into the cytoplasm which trigger the SASP in senescence. Finally, extracellular matrix also changes with ageing, which greatly alters cell behaviour. 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. The field of mechanobiology and its intersection with ageing is thus very promising in terms of ‘rejuvenation’.
5) Inflammation: Inflammageing, age-dependent chronic inflammation, is implicated in a wide range of age-related diseases. Ageing correlates with high, levels of inflammatory mediators in the blood, such as IL-1, IL-6, C-reactive protein, IFNα, and several others. 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.