Figure 2.

Potential intercellular mechanisms related to senescent cells specific reprogramming. Senescence in adipose precursor cells can be improved directly or indirectly (via reduced p21 and p16 pathways by overexpression of Sirt1 [43,55]) by doxycycline-induced overexpression of OSKM. The reversal of senescence by reprogramming can comprehensively improve senescence indicators (decrease in p16, p21, senescence-associated β-galactosidase, etc.) and can, at the same time, ameliorate senescence-associated secretory phenotypes (decreased Mcp-1 and Il-6, MMP13) and even improve histone methylation status (decrease in H3K9me3, H4K20me3) [31]. With the rejuvenation of adipose tissue (telomere lengthening, phenotypic rejuvenation remodelling, and promotion of gene damage repair), the upregulation of adipocyte glutaminase 1 [56] is reversed and the tissue is therefore rescued from the glutamine depleted state caused by ageing. Increased levels of glutamine will improve the chronic inflammatory state associated with ageing on a systemic scale by reducing the transcription of pro-inflammatory genes in macrophages in adipose tissue [48]. This means that the production of senescence-associated secretory phenotypes is reduced, thereby favouring the maintenance of a youthful state in surrounding fibroblasts, adipocytes, and themselves. The reprogramming also promotes the production of secretory eNAMPT in extracellular vesicles. By altering the NAD+ content of cells to regulate their mitochondrial metabolic state and redox homeostasis, eNAMPT promotes the rejuvenation of various cells throughout the body (improves pancreatic and hypothalamic secretion phenotypes, thereby amplifying anti-ageing effects via hormones) [49,57]. Macrophage rejuvenation not only improves the rejuvenation of the systemic secretory phenotype but also attenuates NAD⁺ degradation through reduced CD38 expression [11]. This may have a synergistic anti-senescence effect with eNAMPT. NAD⁺ and a rejuvenated secretory phenotype (possibly through metabolic reprogramming or cell rejuvenation via ERK–AMPK regulation of P16 and P53) improve the GST secretory capacity of fibroblasts. Delivery of GST to organs throughout the body via extracellular vesicles improved cellular redox homeostasis, resulting in a promising anti-ageing effect (improves liver redox status and kidney ageing) [51]. Taken together, local reprogramming through systemic cellular communication (eNAMPT, YSAP, and GST, etc.) produces synergistic anti-ageing effects (improvement in redox and metabolic imbalances caused by mitochondrial senescence and protein instability caused by ribosomal senescence). However, it is worth noting that further studies are needed to determine whether reprogramming can produce sufficient alterations in the secretory phenotype and whether intercellular communication can alter the secretory phenotype of adjacent cells. (black arrow: direct stimulatory, round arrow: cycle, dotted arrow: tentative stimulatory, down faded arrow: decrease, up faded arrow: increase; the grey dotted lines depict macro-level improvements on the left and micro-level improvements on the right, both separated by green dotted lines).