Biology subjects

Wordsworth, J.

Publications and source records attributed to Wordsworth, J..

7 recordsLinked to original sources

bioRxiv2026

Why we age: the four process model

HighlightsO_LIDNA damage-induced selection is the underlying cause of ageing. C_LIO_LIFaster metabolising cells naturally spread unless prevented by a deliberate process designed to prevent hyperfunctional diseases like cancer and fibrosis. C_LIO_LIAs a result, slow metabolising mutants reduce the metabolic rate of faster neighbours epigenetically, shifting energy homeostasis to induce insulin resistance, weight gain, inflammation, metabolic syndrome and age-related disease. C_LIO_LIIn post-mitotic tissues, mitochondria are undergoing similar selection and counterselection, contributing to the same metabolic slowdown. C_LIO_LIThe four process model defined by these selection processes explains all major anti-ageing therapies and connects the hallmarks into a mechanistic framework. C_LI Although ageing can be understood in terms of associated hallmarks and biomarkers, the processes which connect and cause these phenotypes are ill-defined. Here we suggest a unifying model of ageing as four distinct processes which connect the major observations and evidence into a single framework. It explains, from a single initial cause to the ultimate outcomes and diseases, why we age and die. We suggest that although DNA damage is crucial to shift homeostasis, ageing itself is not caused by simple DNA damage accumulation. Instead, only specific sites of damage are relevant when they affect selection and the resulting ageing processes. For clarity, each process is given a name. The first process, celerisis, results from the natural course of tissue-level selection for cells with elevated metabolic and proliferative rate. If the damaged DNA site gives the cell a selective advantage, it can spread within the tissue causing hyperfunctional diseases including cancer and fibrosis. However, many ageing phenotypes are more associated with hypofunction. Therefore, we suggest that our tissues have a mechanism to prevent the spread of hyperfunctional cells. In proliferative tissues, a second process, intrinsic ageing, is the result of this defence mechanism induced through cell communication via Notch. Slower metabolising mutants induce epigenetic changes in faster cells, and then epigenetically slowed cells slow other cells, causing gradual metabolic slowdown across tissues. The third process, extrinsic ageing, could then result directly from metabolic slowdown as body cells use less ATP. Mitochondria reduce catabolism, restoring ATP levels by burning less glucose and lipid. Build-up of these fuels in the cytoplasm reduces import, restoring equilibrium but inducing insulin resistance (IR), while the excess fuel is diverted to the adipose, causing weight gain, chronic inflammation, and metabolic syndrome. These outcomes could then combine with intrinsic ageing to induce age-related disease. The final process of mitochondrial selection induces intrinsic ageing of single celled life as well as post-mitotic tissues and organisms. Together, the four processes produce a detailed mechanistic map that explains the evolutionary significance of ageing, removing old paradoxes, and connecting the hallmarks into a causal framework that furthers our understanding. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=176 SRC="FIGDIR/small/701154v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@2873e3org.highwire.dtl.DTLVardef@1d05f0aorg.highwire.dtl.DTLVardef@10fa833org.highwire.dtl.DTLVardef@ebe435_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO C_FIG

systems biology↗

bioRxiv2023

Metabolic slowdown as the proximal cause of ageing and death

Ageing 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.

systems biology↗

bioRxiv2022

Transcriptomic and epigenetic assessment of ageing female skin and fibroblasts identifies age related reduced oxidative phosphorylation is exacerbated by smoking.

Skin ageing has been widely associated with the formation and presence of increasing quantities of senescent cells, the presence of which are thought to reduce cell renewal. This study aimed to identify key factors influencing fibroblast and skin aging using RNA-seq data. Key differences in study designs included known sources of biological differences (sex, age, ethnicity), experimental differences, and environmental factors known to accelerate skin ageing (smoking, UV exposure) as well as study specific batch effects which complicated the analysis. To overcome these complications samples were stratified by these factors and differential expression assessed using Salmon and CuffDiff. Stratification of female fibroblast and skin samples combined with female specific normalisation of transcriptomic and methylation data sets increased functional enrichment and consistency across studies. The results identify the importance of considering environmental factors known to increase the rate of ageing (smoking status of donors, and UV-exposure status of skin and fibroblast samples) both independently and in combination for the identification of key ageing signatures. The results identified that in old (> 65) female skin decreases in the expression of transmembrane ion transporters coincide with increased methylation of oxidoreductases, and consequently reductions in respiration. This was further evidenced in old fibroblasts from smokers which identified reductions ion homeostasis, and the transcription of mitochondrial tRNAs, that were accompanied by reduced mitochondrial fission, reduced lipid catabolism and reduced immune signalling. These changes occurred in combination with reductions in cell proliferation, adhesion, ECM organisation, cell movement, cytoskeleton organisation and circulatory system development. Middle and old aged skin without environmental stratifications identified decreased expression of transmembrane ion transporters occurred alongside reductions in keratinisation, reduced mitochondrial fission, and this was associated with reduced metabolism (specifically carbohydrates), and consequently a reduction in the production of lipids (phospholipids for membranes and others) occured, exacerbating ion homeostasis issues at a keratinocyte level. Interestingly in skin the combined impacts of UV-exposure, smoking and ageing yielded different results, increased expression of calcium homeostasis genes, cell adhesion molecules (integrins), structural membrane constituents (loricrin, mucins, keratins and collagens), increased cornification, as well as structural cytoskeletal molecules (KRTAPs). This occurred alongside increased expression of genes involved in skin peeling (kalikriens), proliferation and differentiation, glycosylation, oxidative stress, autophagy, lactose metabolism, and lipid catabolism. Aged UV-exposed skin from smokers is on the whole more fibrous, with cells showing significant cell membrane and cytoskeletal structural changes, similar to those seen in skin cancers. Interestingly in non-UV-exposed skin from smokers most of these processes were reduced, and in within age group comparisons of smokers they were also reduced, suggesting that smoking reduced skin development and regeneration. Female specific analysis of smokers from different age groups enrichment results identified additional factors relating to tissue development, cell adhesion, vasculature development, peptide cross-linking, calcium homeostasis, cancer and senescence, leading to age related declines skin structure and function. Interestingly many diseases and infections with overlapping molecular consequences, (ER Ca2+ stress, reduced protein targeting to membranes) including human cytomegalovirus and herpes simplex virus are identified by the age only analysis, suggesting that viral infections and ageing have similar molecular consequences for cells.

bioinformatics↗

bioRxiv2022

Systematic Analysis and Model of Fibroblast Senescence Transcriptome

Cellular senescence is a diverse phenotype characterised by permanent cell cycle arrest and an inflammatory senescence associated secretory phenotype (SASP). Typically, senescent cells are removed by the immune system. This process becomes dysregulated with age and senescent cells accumulate leading to chronic inflammatory signalling. Identifying senescent cells is challenging due to the heterogeneity of senescence, and senotherapy often requires a combinatorial approach. Here we have taken an integrative approach to investigate senescence development at the transcriptomic and protein level. We systematically collected 119 transcriptomic datasets related to human fibroblasts, forming an online database describing the relevant study variables which users can filter to select variables and genes of interest. Our own analysis of the database identified 28 genes significantly up- or downregulated across four senescence types (DNA-damage induced senescence (DDIS), oncogene-induced senescence (OIS), replicative senescence, and bystander induced senescence); 14 genes consistently downregulated, 10 genes consistently upregulated and 4 genes regulation dependent on senescence type. We also found gene expression patterns of conventional senescence markers were highly specific and reliable for different senescence inducers, cell lines, and timepoints. Conclusions of existing studies based on single datasets were supported such as differences in p53 and inflammatory signals between DDIS and OIS. However, contrary to some early observations, both p16 and p21 mRNA levels appeared to rise quickly, depending on senescence type, and persist for at least 8-11 days. Additionally, little evidence was found to support an initial TGF-{beta}-centric SASP. To support our transcriptomic analysis, we computationally modelled temporal protein changes of core senescence proteins in DDIS and OIS, as well as performed knockdown interventions. We conclude that while universal biomarkers of senescence are difficult to identify, conventional senescence markers follow predictable profiles and construction of a workflow for studying senescence could lead to more reproducible data and understanding of senescence heterogeneity.

systems biology↗

bioRxiv2022

Transcriptomic and epigenetic assessment of ageing male skin identifies disruption of Ca2+ homeostasis; exacerbated by smoking and UV exposure

Skin ageing has been widely associated with the formation and presence of increasing quantities of senescent cells, the presence of which are thought to reduce cell renewal. This study aimed to identify key factors influencing fibroblast and skin aging in European males using RNA-seq data. Key differences in study designs included known sources of biological differences (sex, age, ethnicity), experimental differences, and environmental factors known to accelerate skin ageing (smoking, UV exposure) as well as study specific batch effects which complicated the analysis. To overcome these complications samples were stratified by these factors and differential expression assessed using Salmon and CuffDiff. Functional enrichment and consistency across studies, stratifications and tools identified age related alterations in the transcriptomes of fibroblasts and skin. Functional enrichment of results identified alterations in protein targeting to membranes and the ER, and altered calcium homeostasis in aged fibroblasts. Extension to skin controlled for differences in fibroblast culturing methods confirming transient age related alterations in intracellular calcium homeostasis. In middle aged males (40-65) increased keratinisation, skin, epithelial and epidermal development was seen in conjunction with alterations to ER Ca2+ uptake, leading to the identification of related processes including; an unfolded protein response, altered metabolism, increased MMP expression, and altered Ca2+ handling, which were further exacerbated by UV-exposure. Interestingly the genes and processes subsequently decreased in old males (> 65), which exhibited signs of increased senescence. Extension to Illumina 450k array data from ageing skin uncovered evidence of epigenetic regulation; genes and isoforms with overlapping differentially methylated CpGs were differentially expressed. Smoking led to additional enrichment of genes relating to tissue development, cell adhesion, vasculature development, peptide cross-linking, calcium homeostasis, cancer and senescence. The results consistently identified alterations in ER and golgi Ca2+ uptake, which disrupt intracellular and extracellular calcium gradients that regulate metabolic and differentiation signalling in skin and fibroblasts, leading to age related declines skin structure and function. Interestingly many diseases and infections with overlapping molecular consequences, (ER Ca2+ stress, reduced protein targeting to membranes) including COVID-19 are identified by the analysis, suggesting that COVID-19 infection compounds pre-existing cellular stresses in aged males, which could help explain higher COVID-19 mortality rates in aged males, as well as highlighting potential ways to reduce them.

bioinformatics↗

bioRxiv2022

Cell Senescence-Independent Ageing of Human Skin

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 -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.

molecular biology↗

bioRxiv2022

The damage-independent evolution of ageing by selective destruction

Ageing is currently 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.

evolutionary biology↗