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Ageing can be defined as a time-dependent decline in the functionality of the body. At the cellular level, its essence can be seen as a gradual loss of normal cell function accompanied by a series of ageing phenotypes. Breaking the dominance of the senescent microenvironment in the senescent organism and changing this balance to one dominated by the rejuvenating microenvironment has the opportunity to reprogram the metabolism of senescent cells and thus break the characteristic cycle of senescence within senescent cells.
Partial reprogramming simultaneously lengthens telomeres, inhibits p53, and restores mitochondrial function [1]. Interestingly, the telomerase reverse transcriptase overexpression in transgenic mice (Sp53/Sp16/SArf/Tg Tert mice) showed improved tumour resistance and was found to prevent ageing-related degeneration (mainly atrophy) and inflammatory processes, higher blood levels of IGF1, and a reduction in γ-H2AX foci. Increased glucose tolerance and neuromuscular coordination cause a longer average lifespan [2]. The telomere–p53–PGC pathway and its downstream gene network regulate the functional state of multiple organs and ageing: increased levels of p53 (Trp53) lead to inhibition of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α). The germline deletion of p53 fully restores PGC network expression; PGC-1α expression restores mitochondrial respiration, cardiac function, and glucose allosterism [3]. Furthermore, reducing peroxisome proliferator-activated receptor-gamma coactivator-1beta (PGC-1b) attenuates cellular senescence-related phenotypes [4]. This implies that short-term cyclic expression of OSKM can rejuvenate senescent cells’ epigenome in vivo, reduce p16Ink4a and SASP, and affect various senescence-related regulatory pathways (such as mitochondria dysfunction, DNA damage, impaired protein folding, telomere shortening, and inflammation [1]), thus exerting a synergistic anti-ageing effect.
Due to the “asynchronous” character of ageing, senescent cells reprogramming preferentially affects the tissues that are first influenced by ageing (e.g., adipose tissue, the immune system, and fibroblasts [5][6]). The researchers, therefore, start their discussion with adipose tissue (Figure 1). Ageing is often accompanied by a decline in subcutaneous adipocytes marked by the depletion of adipose precursor cells [7], which in turn causes a change in fat tissue distribution—i.e., more visceral white fat and less brown fat [8][9] as well as ectopic fat deposits [10]. This transformation leads to a vicious circle of producing an ageing microenvironment through an imbalance in the inflammatory state and cellular metabolic state associated with ageing and, consequently, a disruption of cellular homeostasis (proteostasis) [11].Figure 1. 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 [8][12]) 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) [1]. With the rejuvenation of adipose tissue (telomere lengthening, phenotypic rejuvenation remodelling, and promotion of gene damage repair), the upregulation of adipocyte glutaminase 1 [13] 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 [14]. 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) [15][16]. Macrophage rejuvenation not only improves the rejuvenation of the systemic secretory phenotype but also attenuates NAD+ degradation through reduced CD38 expression [17]. 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) [18]. 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). (Created with BioRender.com)
Senescence of adipose precursor cells (caused by sirtuin 1 reduction) leads to the accumulation of senescent adipocytes [8], which secrete pro-inflammatory factors that constitute the first part of the senescent microenvironment and cause chronic inflammatory infiltration of adipose tissue [19]. As ageing redistributes fat (visceral fat increases), senescent adipose tissue carries the chronic inflammatory state associated with senescence (Mcp-1 and Il-6) throughout the body and gradually accumulates.
On the whole SASP is detrimental. For example, less than 1% of senescent preadipocytes can cause extensive physical dysfunction in young mice [33]. The killing of adjacent normal cells by SASP affects organ function [34], causing secondary senescence and increasing the accumulation of senescent cells that cause a variety of chronic inflammation/diseases [35] (senescent cells themselves are stalled in replication, so their primary cause of increased senescence is secondary senescence [34]). The anti-apoptotic capacity of senescent cells also increases the accumulation of senescent cells, and this property also protects these cells from SASP (creating a vicious circle) [36]. Targeted reprogramming of these cells may kill cells by breaking the anti-apoptotic capacity of senescent cells (it has been demonstrated in vivo in acute myeloid leukaemia cells, where short-term activation of OSKM expression induces apoptosis in leukaemic cells with little effect on normal haematopoietic stem and progenitor cells [37]). However, another possibility is to retain the beneficial components while eliminating the harmful ones (senescent cells are heterogeneous, and one subpopulation is beneficial for reprogramming and regeneration [38]). The validation of this hypothesis is one of the valuable directions for future research, so this section will comment on the beneficial potential of SASP.
Epigenetics, characterized by acetylation and methylation (especially methylation of histone and the cytosines of CpG dinucleotides [48][49]), plays an essential role in cellular ageing. Thus, the “epigenetic clock (using the key age-related CpGs in a weighted linear model to predict chronological age)” might be indicative of biological age [35]. In addition, multiple studies have shown that epigenetic rejuvenation is possible through partial reprogramming, as reflected by age-deceleration in epigenetic clocks [35]. Therefore, epigenetic remodelling might be one of the most important ways to achieve a synergistic reversal of ageing. A genome-wide knockdown screen of human embryonic stem cells carrying a premature ageing mutation (CRISPR-Cas9-based) revealed that inactivation of the histone acetyltransferase KAT7 could inhibit p15INK4b transcription by reducing acetylation of histone H3 lysine 14 (H3K14) and is anti-ageing [50]. Reprogramming resets telomeres in supercentenarian cells, implying its massive role in cell rejuvenation [51]. Even with extensive epigenetic defects, reprogramming can still reset the epigenetic pattern to a revitalized pluripotent state [52].