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Review
. 2023 Mar 14;8(1):116.
doi: 10.1038/s41392-023-01343-5.

Cellular rejuvenation: molecular mechanisms and potential therapeutic interventions for diseases

Shuaifei Ji #  1 , Mingchen Xiong #  1 , Huating Chen  1 , Yiqiong Liu  1 , Laixian Zhou  1 , Yiyue Hong  1 , Mengyang Wang  1 , Chunming Wang  2 , Xiaobing Fu  3 , Xiaoyan Sun  4
Affiliations
Review

Cellular rejuvenation: molecular mechanisms and potential therapeutic interventions for diseases

Shuaifei Ji et al. Signal Transduct Target Ther. .

Abstract

The ageing process is a systemic decline from cellular dysfunction to organ degeneration, with more predisposition to deteriorated disorders. Rejuvenation refers to giving aged cells or organisms more youthful characteristics through various techniques, such as cellular reprogramming and epigenetic regulation. The great leaps in cellular rejuvenation prove that ageing is not a one-way street, and many rejuvenative interventions have emerged to delay and even reverse the ageing process. Defining the mechanism by which roadblocks and signaling inputs influence complex ageing programs is essential for understanding and developing rejuvenative strategies. Here, we discuss the intrinsic and extrinsic factors that counteract cell rejuvenation, and the targeted cells and core mechanisms involved in this process. Then, we critically summarize the latest advances in state-of-art strategies of cellular rejuvenation. Various rejuvenation methods also provide insights for treating specific ageing-related diseases, including cellular reprogramming, the removal of senescence cells (SCs) and suppression of senescence-associated secretory phenotype (SASP), metabolic manipulation, stem cells-associated therapy, dietary restriction, immune rejuvenation and heterochronic transplantation, etc. The potential applications of rejuvenation therapy also extend to cancer treatment. Finally, we analyze in detail the therapeutic opportunities and challenges of rejuvenation technology. Deciphering rejuvenation interventions will provide further insights into anti-ageing and ageing-related disease treatment in clinical settings.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
The milestone events for cellular rejuvenation research advances. Starting with the 1934 discovery of the influence of dietary restriction on lifespan extension, important findings on the subject of cellular rejuvenation are emphasized. More recently, the senolytics development and reprogramming technology have been widely applied for cellular rejuvenation. rhEGF recombinant human epidermal growth factor, iPSCs induced pluripotent stem cells, AMPK 5’-AMP-activated protein kinase, NF-κB nuclear factor-κB, STAT3 signal transducer and activator of transcription 3, mTOR mammalian target of rapamycin. Created with BioRender.com
Fig. 2
Fig. 2
The epigenetic states of ageing and rejuvenation. Ageing and rejuvenation can be affected by intrinsic epigenetic alterations and genetic instability, like DNA methylation and chromatin remodeling. Moreover, many extrinsic factors, like microenvironmental cues, intercellular communication, and systemic factors, can also impact the epigenetic states of ageing and rejuvenation. miRNAs microRNAs, lncRNAs long noncoding RNAs, ECM extracellular matrix. Created with BioRender.com
Fig. 3
Fig. 3
The target signaling pathways for cellular rejuvenation. Target signaling pathways for cellular rejuvenation are listed according to their biological functions. Many interventions, like dietary restriction and drugs, improve metabolism and extend longevity through nutrient-sensing pathways. In addition, targeting the pathways of damage-induced and developmental senescence can regulate the cell cycle and alleviate age-associated phenotypes. Modulating many inflammation pathways also provides an effective route to rejuvenation. IGF-1 insulin-like growth factor 1, PI3K phosphoinositide 3-kinase, AKT protein kinase B, AMPK 5’-AMP-activated protein kinase, NF-κB nuclear factor-κB, STAT3 signal transducer and activator of transcription 3, mTOR mammalian target of rapamycin, SIRTs sirtuins, FOXO forkhead homeobox type protein O, ROS reactive oxygen species, TGF-β transforming growth factor-β, CDKs cyclin-dependent kinase. Created with BioRender.com
Fig. 4
Fig. 4
Schematic overview of strategies for cell rejuvenation. Various strategies have been developed for cell rejuvenation that leverage intrinsic and extrinsic factors, including epigenetic reprogramming, genetic enhancement, autophagy modulation, and metabolic manipulation. Furthermore, small molecules, growth factors and cytokines, blood factors, iPSC technology, clearance of senescent cells and SASP, microenvironment regulation, and circadian clock modulation can also exert great influences on cell rejuvenation. iPSCs induced pluripotent stem cells, SASP senescence-associated secretory phenotype. Created with BioRender.com
Fig. 5
Fig. 5
Reprogramming approaches for rejuvenation. The iPSC-mediated cell reprogramming is a protocol that somatic cells are first dedifferentiated into iPSC and then differentiated into the desired somatic cells. Partial reprogramming refers to a short exposure to Yamanaka factors only generates intermediates with high plasticity. Transforming somatic cells from one lineage to another without transitioning through intermediary pluripotent stages is known as direct lineage reprogramming. iPSCs induced pluripotent stem cells, ESCs embryonic stem cells; Oct3/4, Sox2, Klf4, c-Myc, OSKM. Created with BioRender.com
Fig. 6
Fig. 6
The mechanisms for cellular reprogramming in cancer. Cancer cell reprogramming treatment aims to convert the malignancy to benignity or provide a therapeutic target to inhibit the formation of CSCs. Yamanaka factors-mediated iPSCs technology has been recognized as a common method for the conversion of cancer cells to benign pluripotent cells, and cancer cells-derived iPSCs can re-differentiate into functional cells with less malignancy and free of tumorigenic potential. Cancer cells also can be directly reprogrammed into benign cells via various reprogramming strategies, such as lineage-specific factors, small molecules, microRNAs, and exosomes. Responsive cellular reprogramming based on EMT contributes to CSCs formation, which mediates the initial, progression, metastasis, and post-treatment recurrence. The role of cellular reprogramming in the formation of CSCs suggests that anti-cellular reprogramming strategies may be considered as a therapeutic alternative in cancer treatment. EMT Epithelial–mesenchymal transition. Created with BioRender.com
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