The damage-independent evolution of ageing by selective destruction

Wordsworth, James; Keefe, Hannah O’; Clark, Peter; Shanley, Daryl P.

doi:10.1016/j.mad.2022.111709

Cited by 4 publications

(1 citation statement)

References 72 publications

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“…One possibility is that homeostasis has shifted toward reduced ECM production and slower metabolism; consistent with a different model of ageing we have recently described as selective destruction theory (SDT) [57]. SDT predicts that many cells will undergo a reduction in metabolism that may manifest in lower basal rates of anabolic activity such as ECM production.…”

Section: Discussionmentioning

confidence: 59%

Cell Senescence-Independent Changes of Human Skin Fibroblasts with Age

Fullard,

Wordsworth,

Welsh

et al. 2024

Cells

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Skin ageing is defined, in part, by collagen depletion and fragmentation that leads to a loss of mechanical tension. This is currently believed to reflect, in part, the accumulation of senescent cells. We compared the expression of genes and proteins for components of the extracellular matrix (ECM) as well as their regulators and found that in vitro senescent cells produced more matrix metalloproteinases (MMPs) than proliferating cells from adult and neonatal donors. This was consistent with previous reports of senescent cells contributing to increased matrix degradation with age; however, cells from adult donors proved significantly less capable of producing new collagen than neonatal or senescent cells, and they showed significantly lower myofibroblast activation as determined by the marker α-SMA. Functionally, adult cells also showed slower migration than neonatal cells. We concluded that the increased collagen degradation of aged fibroblasts might reflect senescence, the reduced collagen production likely reflects senescence-independent processes.

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Section: Discussionmentioning

confidence: 59%

Cell Senescence-Independent Changes of Human Skin Fibroblasts with Age

Fullard,

Wordsworth,

Welsh

et al. 2024

Cells

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Cell Senescence-Independent Ageing of Human Skin

Wordsworth

Fullard

Welsh

et al. 2022

Preprint

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Skin ageing is defined in part by collagen depletion and fragmentation that leads to a loss of mechanical tension. This is currently believed to reflect, in part, the accumulation of senescent cells. We compared the expression of genes and proteins for components of the extracellular matrix (ECM) as well as their regulators and found that senescent cells produced more matrix metalloproteinases (MMPs) than proliferating cells from adult and neonatal donors. This was consistent with senescent cells contributing to increased matrix degradation with age; however, cells from adult donors proved significantly less capable of producing new collagen than neonatal or senescent cells, and they showed significantly lower myofibroblast activation as determined by the marker α-SMA. Functionally, adult cells also showed slower migration than neonatal cells. We concluded that while increased collagen degradation with age might reflect senescent cell accumulation, the reduced collagen production that prevents the skin from maintaining homeostasis must reflect senescence-independent processes.

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Metabolic slowdown as the proximal cause of ageing and death

Wordsworth

Nielsen

Fielder

et al. 2023

Preprint

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SummaryAgeing results from the gradual loss of homeostasis, and there are currently many hypotheses for the underlying initial causes, such as molecular damage accumulation. However, few if any theories directly connect comprehensive, underlying biological mechanisms to specific age-related diseases. We recently demonstrated how a specific maintenance system impeding overactivity disorders such as cancer might undergo positive selection while still resulting in a gradual homeostatic shift toward slower metabolism. Here we connect this metabolic slowdown, via a series of unavoidable homeostatic shifts, to the hallmarks of ageing, including mitochondrial dysfunction, insulin resistance (IR), weight gain, basal inflammation, and age-related diseases such as atherosclerosis. We constructed the fuel and energy model (FEM) based on these shifts and found that ageing via metabolic slowdown could explain not only the effects of anti-ageing interventions such as rapamycin and calorie restriction, but many of the paradoxes of ageing that currently defy alternative theories.

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The damage-independent evolution of ageing by selective destruction

Cited by 4 publications

References 72 publications

Cell Senescence-Independent Changes of Human Skin Fibroblasts with Age

Cell Senescence-Independent Changes of Human Skin Fibroblasts with Age

Cell Senescence-Independent Ageing of Human Skin

Metabolic slowdown as the proximal cause of ageing and death

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