BBSRC UKAN Researchers on Ageing: Approaches to Ageing Issues

Immune senescence is typified by alterations in T cell memory, such as the accumulation of highly differentiated end-stage memory T cells, as well as a constitutive low-grade inflammation, which drives further immune differentiation and exacerbates disease. We have recently demonstrated that senescent T cells are highly heterogeneous and hypothesised this to be due to the mechanism by which senescence is triggered. We show here that unhealthy ageing leads to a prematurely aged phenoptype driven by environmental factors rather than repeated turnover. Changes in mitochondrial dynamics and metabolism better defines the heterogeneity in senescent T cells with nutrient sensing pathways converging to regulate immune senescence. 

Down syndrome (DS) is the most common form of chromosomal trisomy that is characterised by distinct facial features, intellectual disability and predisposition to distinct co-morbidities. DS is considered a proaging disease associated with accelerated ageing and immunosenescence. Diabetes have also been associated with advanced immune aging. We studied the prevalence of obesity and diabetes in DS using a large national UK health database (UK Clinical Practice Research Datalink data from 1990 to 2020). Analysing 9,917 patients with DS and 38,266 control patients, we showed that at younger ages, the incidence of diabetes in patients with DS is up to four times that of control patients. Peak mean BMI is higher and established earlier in DS, contributing to Type 2 Diabetes risk. We are currently investigating the mechanisms associated with this predisposition and the long-term consequences through the DS life course and ageing.  

In 1951 Peter Medawar delivered his famous inaugural lecture “An Unsolved Problem of Biology” which laid the conceptual groundwork for all modern evolutionary theories of ageing.  Since then significant progress has been made in uncovering the processes controlling how organisms age and although these fundamental mechanistic insights are directly informing clinical trials in humans (for example the use of senolytics or drugs which modulate nutrient sensing pathways) some problems in human ageing remain unsolved.
In homage to Medawar this abstract will discuss three such problems currently under consideration by the BLAST network.  Firstly, that although there is broad consensus concerning the evolution of ageing in general the evolution of human ageing as a particular case remains much less clear (particularly with regards to the effects of extensive genetic drift and the origins and value of menopause).   Secondly that although evolutionary theories predict the emergence of mortality plateaus at late ages our current mechanistic “Hallmarks” (e.g. cell senescence) do not readily allow for the emergence of such steady states; and lastly that the mechanisms of survival of centenarians appear to challenge many conventional aspects of the biology of senescence.  Some possible routes to the solution of these problems will be discussed.

The skin, our largest organ, undergoes significant structural and functional changes with age that can be accelerated by both extrinsic and intrinsic factors. The epidermis gets thinner due to decreased proliferation, and dryer due to changes in lipid production and composition. In the dermis collagen crosslinking leads to tissue stiffening and the biomechanical properties of the extracellular matrix. Another hallmark is chronic inflammation leading to elevated proinflammatory cytokines, proteolytic enzymes, and reactive oxygen species, increasing oxidative stress and damage to DNA, proteins and lipids. The skin has an essential protective role and maintaining an effective barrier function is crucial to survival. Incidence of non-healing chronic wounds is significantly increased in the elderly, with high risk of infection and life-threatening complications e.g. sepsis. 

Recently there has been increasing interest in the role of the skin microbiome in the maintenance of a healthy skin barrier. The skin microbiome represents the second largest microbiome (after the gut) and varies across different anatomical regions e.g. face, feet, arms, scalp, axilla. The skin microbiome changes across the life course, starting with the mode of delivery at birth, impact of sex steroids at puberty and then menopause, to changes with advancing age. Changes in the gut and oral microbiome have been linked to disease states, but our understanding of the skin microbiome is still in its infancy. With SMiHA our aim is bring together academics, clinicians and industry to advance our understanding of the importance of the skin microbiome in healthy ageing.

Plasma membrane damage (PMD) affects all cell types and can lead to either cell recovery or death. Here, we show that PMD can also cause cellular senescence, a state of stable cell cycle arrest associated with aging and age-related diseases. In yeast, PMD shortens replicative lifespan, and upregulation of plasma membrane repair by upregulating PMD repair factors can extend it. In human fibroblasts, PMD induces premature senescence via the Ca2+-p53 pathway rather than the DNA damage response, and upregulation of PMD repair factors suppresses it. This study identifies a previously underappreciated senescent cell type induced by PMD and highlights its potential role in organisms.

Decline in mitochondria activity is a hallmarks of aging. However, it is still unclear whether this decline corresponds to a reduction in the extent of axonal translation in aging neurons. We found a significant decrease in the number of active mitochondria and in the percentage of moving mitochondria in axons of sensory neurons isolated from late-adulthood mice. This decrease was mirrored by a ATP-dependent decrease in axonal cytoplasm viscosity. RNA granules stained by G3BP1 were also fewer in number and forming bigger aggregates in sensory neurons isolated from late-adulthood mice. Functionally, this resulted in a decrease in axonal translation as well in the number of translational foci in aging neurons. We also showed that attempting to increase ATP synthesis had a positive effect on axonal translation in aging neurons. We think that this research sheds light on axonal translation in aged neurons and its relationship with energy sources inside the axonal compartment, which might present an opportunity for therapy in the future. 

Cell division is a fundamental process in all living organisms. The mechanism of cell division has been extensively studied in simple model systems including yeast and cultured cells. However, it remains unclear how large embryonic cells divide correctly and how it is affected by aging. Recently, we have established live functional assay systems by combining live imaging and auxin-inducible degron-based protein knockdown technology in medaka embryos (Kiyomitsu et al., Nature Communications 2024). In this mini-symposium, I share our recent findings about unique features of early embryonic divisions and would like to receive feedback on whether or how our system contributes to aging-related research.

It is becoming clear that the accumulation of ‘senescent cells’ that are induced by various stressors including DNA damage and show characteristics such as irreversible arrest of cell proliferation and secretion of bioactive molecule (SASP) is important for anti-tumorigenesis as well as the onset and progression of aging-related diseases. Studies show that removing senescent cells in mice can improve age-related conditions and extend lifespan, indicating their negative impact. However, recent research has revealed that senescent cells are also induced during embryogenesis, wound healing, and acute tissue injury, where they are typically cleared by immune cells. The molecular mechanisms driving the differences in senescent cell dynamics remain unclear. This presentation discusses the findings on senescent cells during acute liver injury using a mouse model for single-cell level analysis, comparing these cells with those in chronic liver injury to provide insights into their role in disease.