Altered immunometabolism in adipose tissue: A major contributor to the ageing process?

As humans continue to live for longer, the prevalence of age-associated diseases, such as diabetes, cancer and neurodegenerative conditions, continues to increase (Pérez et al. 2016). Therefore, it is becoming increasingly important to understand the biological mechanisms governing the normal ageing process. Although the exact mechanisms of ageing are still unclear, inflammation has been identified as a prominent contributor (Pérez et al. 2016). Notably, both ageing and obesity share numerous biological dysfunctions, including increased chronic inflammation and metabolic disease risk (Tam et al. 2020). In obesity, dysfunctional adipose tissue is a driving force of elevated local and systemic inflammation by secreting an array of inflammatory cytokines (Tam et al. 2020). However, there is limited evidence elucidating the role of adipose tissue in normal human ageing. Moreover, evidence linking systemic and tissue-specific immunometabolic outcomes is also lacking in human ageing studies. In a recent issue of The Journal of Physiology, Trim et al. (2021) explored the immunometabolic changes in abdominal subcutaneous adipose tissue, skeletal muscle and blood with age by comparing young (27 ± 4 years) and older (66 ± 5 years) physically active males without obesity (Fig. 1). Using sophisticated methods, including flow cytometry and RNA-sequencing, they demonstrated that: (i) in healthy, active, older adults, the immunometabolic changes found in adipose tissue and skeletal muscle may precede the systemic manifestation, including a two-fold greater T-cell presence than in young adults; (ii) the changes were tissue-specific, with the most significant changes noted in adipose tissue, followed by skeletal muscle, and then the blood; and (iii) adipose tissue from older adults had increased inflammatory transcripts, which were absent in skeletal muscle. Here, we aim to explore the presented data and extend the discussion to address whether altered immunometabolism in adipose tissue could be a key contributor to the ageing process. Immunometabolic changes with ageing in blood, skeletal muscle and subcutaneous adipose tissue reported by Trim et al. (2021). ↑, Increased compared to young adults. ↓, Decreased compared to young adults. ↔, No change compared to young adults. *Proportions are based on the analysis of 14 pro-inflammatory adipokines and five anti-inflammatory adipokines. Adipokines were measured in plasma and in culture media from ex vivo cultured adipose tissue explants. †50% and 0% of the upregulated transcripts related to pro-inflammatory pathways in adipose tissue and skeletal muscle, respectively. ‡Based on the gene/protein expression of InsR(β), Akt2, AS160 and GLUT4. Only Akt2 protein expression was unchanged in adipose tissue. Trim et al. (2021) identified numerous changes within adipose and skeletal muscle tissues with ageing, which could further be associated with the ageing process. Immunological differences were examined with the use of flow cytometry. In doing so, numerous challenges were overcome, including those presented by the oily nature of adipose tissue, which can cause macrophage autofluorescence and low immune cell yields. Their flow cytometry experiment had many strengths, including minimal population overlap, the use of a wide range of immune cell markers and the need for only a small amount of initial tissue. Their results showed that T-cells, granulocytes and macrophages were all elevated with age in skeletal muscle, whereas only T-cells and granulocytes were elevated in adipose tissue (Trim et al. 2021). Increased macrophage and T-cell levels have been directly implicated in the inflammatory pathways associated with ageing, leading to insulin resistance and eventual metabolic diseases (Tam et al. 2020). The increase in T-cells could be significant in the ageing process, having been identified in both aged adipose tissue and skeletal muscle. Furthermore, because recent evidence showing that T-cells infiltrate adipose tissue before macrophages in obesity (Tam et al. 2020), the elevated T-cells in the adipose tissue of older adults could be an initial step in age-associated metabolic disease. In addition to changes in immune cell content, Trim et al. (2021) compared inflammatory profiles of blood and adipose tissue secretions. A greater number of inflammatory cytokines were elevated with age in adipose tissue secretions than in the blood, suggesting that these cytokines are primarily acting locally within adipose tissue. Notably, a pro-inflammatory adipose tissue secretory profile is a characteristic of cellular senescence (cellular ageing), the accumulation of which is associated with many age-related diseases (Almendáriz-Palacios et al. 2020). Furthermore, it is known that the secretion of pro-inflammatory proteins further induces senescence in surrounding cells, which propagates the systematic ageing process (Almendáriz-Palacios et al. 2020). Unexpectedly, adiponectin, a hormone considered as an anti-inflammatory in nature, was increased in the circulation of older individuals compared to young. Because adiponectin expression is negatively regulated by pro-inflammatory cytokines, the adipose tissues from older adults with elevated pro-inflammatory cytokine secretions were expected to show a lower adiponectin level. However, there is increasing evidence of an adiponectin paradox whereby high levels of adiponectin are associated with deteriorating metabolic health, low skeletal muscle mass, poor physical functioning and all-cause mortality (Menzaghi & Trischitta, 2018). Although there is not yet sufficient evidence available to know the effect adiponectin is having on healthy ageing, it is certainly an area for future investigation. It has been extensively documented that insulin sensitivity and insulin-like growth factor-1 decrease with age, contributing to metabolic and age-associated diseases (Almendáriz-Palacios et al. 2020). Trim et al. (2021) examined some key proteins involved in insulin signalling pathways and identified lower levels of glucose transporters and insulin receptors in the aged adipose tissue, but not in the skeletal muscle. Although this is in line with the alterations of immune-cell profiles identified in adipose tissue, it is unclear why increased levels of macrophages and T-cells did not have the same impact on insulin signalling proteins in muscle. Perhaps the alterations of immune cells in aged skeletal muscle are resultant of changes in adipose tissue. Significantly, Trim et al. (2021) further examined transcriptomic changes of adipose tissue and skeletal muscle with age, providing initial evidence in the understanding of associations between immunological and genomic changes. Their results revealed that the levels of gene transcripts associated with insulin signalling were different between adipose tissues and skeletal muscles, although no differences were found between young and old groups in both tissues. Additional analyses of the transcription factor binding sites of genes changing in adipose tissue could reveal important protein-mediators in insulin signalling pathways, as well as the inflammasome, which contribute to the role of adipose tissue secretions in ageing. Trim et al. (2021) demonstrated a clear divergence between skeletal muscle and adipose tissue in normal human ageing by providing a robust profiling of immune cell content and transcriptomic changes. Overall, they demonstrated that immunometabolic alterations in adipose tissue are key in mediating the ageing processes. Here, we expanded on this idea by discussing how adipose tissue is central to elevated inflammation and altered gene expressions, and how these alterations are detrimental to the ageing process. To build on the work of Trim et al. (2021), future studies could address the following questions. (i) Given that only males were examined in the current work, are there sex differences in immunometabolic measures of ageing? (ii) In older adults (>66 ± 5 years), do changes observed in adipose tissue present in skeletal muscle? (iii) Given that adipose tissue inflammation is known to differ between adipose tissue depots, how does regional body composition affect tissue specific and systemic inflammation in ageing? (iv) Can secretions from aged adipose tissue induce ageing-associated features in young skeletal muscle via in vitro co-culture systems? By answering these questions, the role of adipose tissue in systematic ageing could be further elucidated. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. The authors declare that they have no competing interests. All authors contributed to the conception of the article, drafting the work and revising it critically. All authors have read and approved the final version of the manuscript and agreed to be accountable for all aspects of the work. No funding was received for this work specifically. KZD is supported by a FRQS Doctoral Award and a R. Howard Webster Foundation Doctoral Fellowship. ZEG is supported by a Vanier Canada Graduate Scholarship. JM is a recipient of an FRQS Doctoral Award and PERFORM Doctoral Fellowship. CW is supported by a CBS-International PhD Graduate Research Assistantship and an International Doctoral Tuition Scholarship from the University of Guelph. The authors recognize that not all relevant articles were cited as a result of reference limitations.