The damage-independent evolution of ageing by selective destruction. (October 2022)

• Record Type: Journal Article
• Authors: Wordsworth, James; O' Keefe, Hannah; Clark, Peter; Shanley, Daryl
• Is Part Of: Mechanisms of ageing and development. Volume 207(2022)
• Publication Date: 2022-10
• Subjects: AGE Advanced glycation end product -- AP Antagonistic Pleiotropy -- AR Aberrantly resistant (to growth stimuli) -- AS Aberrantly sensitive (to growth stimuli) -- ASHM Autoimmune surveillance of hypersecreting mutants -- CFOA Cancer, fibrosis, and overactivity disorders -- CR Caloric restriction -- DST Disposable soma theory -- FRV Fibrosis risk value -- GH Growth hormone -- GM Growth marker (demonstrating growth rate) -- IDH1 Isocitrate dehydrogenase 1 -- IGF-1 Insulin-like growth factor 1 -- MAT Mutation accumulation theory -- MICA MHC class I chain-related protein A -- mTORC1 Mammalian target of rapamycin complex I -- PI3K Phosphoinositide 3-kinase -- RAF Rapidly Accelerated Fibrosarcoma -- SD Selective destruction -- SDT Selective destruction theory -- SNP Single nucleotide polymorphism -- TRV Tumour risk value -- TSC2 Tuberous sclerosis complex 2 -- UD Unselective destruction -- WT Wildtype; Evolution -- Mutant -- Selection -- Theory -- Damage -- Growth; Aging -- Periodicals; Developmental biology -- Periodicals; Aging -- Periodicals; Developmental Biology -- Periodicals; Vieillissement -- Périodiques; Biologie du développement -- Périodiques; Aging; Developmental biology; Periodicals; 612.67
• DOI: 10.1016/j.mad.2022.111709
• Languages: English
• ISSNs: 0047-6374

Abstract

Abstract: Ageing is widely believed to reflect the accumulation of molecular damage due to energetic costs of maintenance, as proposed in disposable soma theory (DST). Here we use agent-based modelling to describe an alternative theory by which ageing could undergo positive selection independent of energetic costs. We suggest that the selective advantage of aberrant cells with fast growth might necessitate a mechanism of counterselection we name selective destruction that specifically removes the faster cells from tissues, preventing the morbidity and mortality risks they pose. The resulting survival advantage of slower mutants could switch the direction of selection, allowing them to outcompete both fast mutants and wildtype cells, causing them to spread and induce ageing in the form of a metabolic slowdown. Selective destruction could therefore provide a proximal cause of ageing that is both consistent with the gene expression hallmarks of ageing, and independent of accumulating damage. Furthermore, negligible senescence would acquire a new meaning of increased basal mortality. Graphical Abstract: ga1 Highlights: Mutant cells with an increased rate of growth have a selective advantage. Such mutant cells would spread and disrupt tissue homeostasis. They must therefore be controlled by a mechanism that selects against faster growing cells. This selective destruction could shift selection and allow slow mutants to spread. The resultant spread of slow-functioning cells could cause metabolic slowdown and ageing.