Table 1.

The cellular rejuvenation used for various disease treatments

Rejuvenation strategy	Specific intervention	Mechanism	Disease treatment	Ref
Cellular reprogramming	Reprogramming to a fully pluripotent state	1. Reprogramming from cancer cells to iPSCs with a benign phenotype 2. iPSCs modeling of diseases 3. The transplantation of iPSCs-derived functional cell	Cancer, AMD, AD, PD, ALS, diabetes, OA, osteoporosis and autoimmune disorders	326,473–480
	Lineage reprogramming	1. Cell replacement therapy of reprogramming-derived functional cells without the need for a pluripotent state 2. Reprogramming cancer cells to differentiated cells to alleviate tumorigenicity	Cancer, diabetes, AD, PD, CAD and fibrosis	438,481–485
	In vivo reprogramming	1. In vivo partial reprogramming (transient expression of pluripotency-associated genes) for epigenetic rejuvenation and the amelioration of organismal phenotype associated with ageing 2. In situ trans-differentiation of targeted cells to functional cells	Ageing, diabetes, tissue regeneration, autoimmune disorders, CAD and fibrosis	272,419,486–488
SCs elimination and SASPs inhibition	Ablation of p16-positive cells	Pharmacological activation of transgene INK-ATTAC to induce apoptosis in p16(Ink4a)-expressing cells	Age-related functional decline of kidney, heart, cartilage and bone	489,490
	Senolytics	The targeted inhibition of the SCAP network to induce SCs apoptosis (e.g., Dasatinib, Quercetin, Fisetin and Navitoclax)	Cancer, diabetes, ageing, fibrosis, osteoporosis, obesity, NDD, CAD, IVDD and CKD	491–495
	Senomorphics	Suppressing the signaling from SCs and reducing systematic inflammation (e.g., p38MAPK inhibitor, JAK inhibitors, rapamycin, glucocorticoids and ILs mAb)	Cancer, diabetes, obesity, NDD, CKD, OA and fibrosis	406,496,497
	Immune clearance	Enhancing the function of immune cell to recognize and kill SCs (e.g., NK cells, MOs and T cells)	Cancer, fibrosis and tissue regeneration	294,498
Stem cells-associated therapy	Restoration of aged stem cell functions	1. Rescuing metabolism homeostasis (e.g., rapamycin, metformin and NMN) 2. Promoting DNA repair and preservation of genome stability (e.g., NMN) 3. Repairing tissue-specific stem cell to replenish the stem cell pool (e.g., HSCs and EpSCs) 4. Regulating extracellular signals (e.g., EVs delivery and neuroendocrine activation) and remodeling ECMs	Hematological disease, ageing, diabetes, ischemia-reperfusion injury, heart failure, AD and retinal degeneration	499,500
	Transplantation of youthful stem cells	1. The differentiation into tissue-specific cell with the stimulation of specific signals and local microenvironment 2. Paracrine effect with the release of soluble cytokines, chemokines and growth factors involved in immune regulation, angiogenesis, anti-apoptosis, anti-inflammation, anti-oxidation and anti-fibrosis	Hematological disease, graft-versus-host disease, organ transplantation, diabetes, inflammatory diseases, and diseases in the liver, kidney, and lung, as well as cardiovascular, bone and cartilage, neurological, and autoimmune diseases	501
Dietary restriction	Time-restricted feeding and calorie restriction	1. Nutrient-mediated mechanisms: metabolic regulators, nutritive metabolism pathways, epigenetic mechanisms and circadian clocks 2. Diet-responsive effectors: the diet-endocrine axis, the diet-immune axis, the diet-gut axis, the diet-senescence axis and the diet-nerve axis.	Metabolic syndrome, CVD, Intestinal malfunction, CKD, NDD, MTB infection, COPD, cancer and tissue regeneration	502
Immune rejuvenation	Activation of immune cells	1. Restoration of aging HSC to increase the number of immune lineages (e.g., myeloid and lymphoid precursors) 2. Rescuing T lymphocytes exhaustion for the reversal of immune-senescence	Cancer, ageing, age-related degeneration of the thymus, RA and tissue regeneration	503,504
	Recapitulation of immune organ	1. Direct differentiation of hESCs/iPSCs into thymic precursor lineage 2. Ectopic thymus regeneration for fibroblasts reprogramming 3. Adult stem cell-derived thymus organoids	Diseases associated with immunodeficiency and autoimmunity	505
Heterochronic transplantation	Parabiosis	Allowing the young and old organisms to share of the blood circulation surgically	Ageing, age-related functional impairment of skeletal muscle, liver and bone, cognization decline	372,377,506
	Blood or cerebrospinal fluid exchange	1. The delivery of rejuvenative factors by young blood injection, human umbilical cord plasma and young cerebrospinal fluid administration 2. The exchange of half old blood plasma with saline-albumin to dilute age-elevated systemic factors	Ageing, age-related impairment in cognitive function and AD	383,507
	Circulating plasma factors	Rejuvenative factors identified by heterochronic transplantation (e.g., GDF11, Apelin, Cadherin13, eNAMPT, SPARCL1, THBS4, TIMP2, Oxytocin, FGF17 and α-Klotho)	Ageing, age-related impairment in cognitive function, skeletal muscle ageing	508–510

HSCs hematopoietic stem cells, EpSC epidermal stem cell, MDSC muscle-derived stem cell, NMN nicotinamide mononucleotide, IVDD Intervertebral disc degeneration, NDD Neurodegenerative disease, CKD Chronic kidney diseases, MTB pulmonary mycobacterium tuberculosis, COPD chronic obstructive pulmonary disease, RA rheumatoid arthritis, AD Alzheimer’s disease, GDF11 circulating growth differentiation factor 11, TIMP2 tissue inhibitor of metalloproteinases 2, FGF17 fibroblasts growth factors 17