Table 1.

Age-related changes in cellular characteristics and behavioral properties.

	Age-Related Changes	Description	Reference
Cell physical property	Cellularity	Cell numbers in tendons are reduced with aging.	[3,32,39,40,41,42,43]
		DNA content does not decrease with aging in horse SDFTs.	[16]
		The TSPC pool is exhausted with tendon aging and degeneration.	[23]
		Possible mechanisms of TSPC aging and degeneration: ROCK pathway, miR-135a, Pin1, and TNMD.	[18,24,25,26]
	Cell morphology	Young TSPCs can show a spindle-like cell shape; aged TSPCs exhibit a star-like flattened appearance.	[18,19,23]
		Young tenocytes have a rounder cell shape, but aged tenocytes have a thinner, more elongated phenotype.	[32,40]
		Aged tenocytes show a higher nucleus-to-cytoplasm ratio and elongated nucleus compared with young tenocytes.	[32,44]
		Tenoblasts become longer and more slender with aging.	[45]
	Cytoskeletal organization	In young TSPCs, only a few dominant fibers span the longitudinal axis of the cells and do not align strictly in parallel. Aged TSPCs show a well-structured actin cytoskeleton and a smoother surface without prominent fibers.	[18,39]
		Aged tendon fibroblasts have fewer stress fibers, which are only present close to the cell periphery.	[17]
	Stiffness	Aged TSPCs are generally stiffer than young TSPCs.	[18,19]
Cell behaviors	Cell adhesion and migration	Slower actin dynamics might contribute to the decreasing migratory capacity of TSPCs during aging.	[14]
		Young tendon fibroblast adhered 30% more efficiently and formed stronger attachment than aged tendon fibroblast. FA proteins displayed different localization in tendon fibroblast with aging.	[17]
	Metabolic activity	There is a reduction in the organelles participating in protein synthesis, e.g., rough endoplasmic reticulum (ER), mitochondria.	[46]
		In rabbit Achilles tendon tissue slices, aerobic glycolysis gradually decreases from the first three months and cellular respiration completely ceases at three years of age, while anaerobic glycolysis is maintained at a similar activity level throughout the whole tendon lifespan.	[22]
		There is a higher GADD153 expression (ER stress-related) in aged tendon fibroblast than in young tendon fibroblast.	[17]
	Cell–cell interactions	Aged TSPCs cell–cell interactions are limited by the downregulation of the ephrins (Eph) receptors EphA4, EphB2, EphB4 and ligand EFNB1.	[31]
	Proliferation (self-renewal) capacity	The proliferation of TSPC is reduced with aging. Cell cycle progression was arrested at G2/M phase in senescent TSPC. These phenomena are associated with the downregulation of cellular senescence-inhibited gene (CSIG) and upregulation of p27.	[14,34]
		The doubling time of aged tendon fibroblast is about three times slower than that of young tendon fibroblast.	[17]
	Differentiation	Aged TSPCs showed reduced stemness, while other groups have shown that young and aged TSPCs were stained positively for three stem cell markers, indicating that this population retains their stemness regardless of age.	[14,34,35]
		In TSPCs, CD44 was upregulated with aging, but CITED2, FOXP1 and Pin1 were downregulated.	[14,26,28]
		The tenogenic differentiation capacity of TSPCs significantly decreases with aging. The p16/miR-217/early growth response factor 1 (EGR1) pathway is involved in the age-related tenogenic differentiation of TSPCs.	[47]
		In an RNA-sequencing analysis, the expression of 325 transcribed elements was significantly distinct between old and young tendons.	[48]
		The mRNA expression levels of collagens and tenogenic markers significantly declined with aging, but contradictory views were mentioned by other authors.	[16,32,41]