Aging puzzle: A closer look on the complex dilemma of autologous stem cell therapy

Table 1 Historical milestones of stem cell-based therapies[8,10-12]

Year	Discovery
1868	The earliest known use is by Ernst Haeckel (1868), referring to unicellular organisms as the origin of multicellularity[10]
1902	First description of hematopoietic progenitor cells by Franz Ernst Christian Neumann and Alexander A Maximov[12]
1939	First report of bone marrow transplantation for aplasmic anemia; first attempt failed
1957	Dr. E Donnall Thomas performed the first allogeneic hematopoietic stem cell transplantation
1958	First transplantation of stem cell for the treatment of radioactive exposure by George Mathe
1960s-1970s	Foundational works on stromal stem cells led by Friendenstein’s team
1972	The successful allogeneic transplants (first successful cases) for aplastic anemia
1981	The first murine ESCs were established by Evans and Kaufman and GR Martin
1991	Stromal stem cells were renamed as “Mesenchymal stem cells” by AI Caplan
1998	James Thomson isolated the first ESCs from human
2007	Discovery of iPSCs by Shinya Yamanaka and Kazutoshi Takahashi
2010	First clinical trial using ESC-derived OPC1 for the treatment of spinal cord injury conducted by Geron (NCT01217008)
2015	First case report of cardiac progenitors produced from human ESCs for severe heart disease
2017	First report of using iPSC-derived retinal cells in treatment of macular degeneration
2022	Reported 10 years follow up data on OPC1 administration for the treatment of spinal cord injury

ESC: Embryonic stem cell; iPSCs: Induced pluripotent stem cells.

Table 2 Characteristics of mesenchymal stem cells supporting their use for age-related disorders

Feature	Benefit for age-related disorders
Multilineage differentiation	Regenerates multiple tissue types damaged by aging
Low immunogenicity	Reduces risk of immune rejection
Immunomodulation	Controls chronic inflammation common in aging
Ease of isolation and expansion	Facilitates clinical application
Exosome secretion	Delivers anti-inflammatory, antioxidant and regenerative factors
Combats oxidative stress	Protects cells from age-related damage
Rejuvenation potential	Restores function of aged stem cells

Table 3 Studies on how donor age affects the regeneration potential of stem cells

	Title of study	Type of cells used	Sample size	Study type	Major findings	Ref.
1	Influence of donor age and comorbidities on transduced human adipose-derived stem cell in vitro osteogenic potential	ADSCs	122	In vitro	Donor age had little effect on self-renewal capacity, proliferation, cell yield, and osteogenic capacity of ADSCs. ADSCs are a reliable resource for gene therapy applications involving both autologous and allogeneic cells	[25]
2	Impact of donor age on the osteogenic supportive capacity of mesenchymal stromal cell-derived extracellular matrix	ADSCs	4	In vitro	Older donors showed reduced osteogenic support	[23]
3	Transplanting cells from old but not young donors causes physical dysfunction in older recipients	ADSCs	12	In vivo	Old ADSCs impaired physical function in recipients	[26]
4	Age affects the paracrine activity and differentiation potential of human adipose-derived stem cells	ADSCs	8	In vitro	Older ADSCs had reduced paracrine function and differentiation	[27]
5	Effect of donor age and 3D-cultivation on osteogenic differentiation capacity of adipose-derived mesenchymal stem cells	ADSCs	11	In vitro	Younger ADSCs showed stronger osteogenesis; older cells declined	[28]
6	Age-related changes in the regenerative potential of adipose-derived stem cells isolated from the prominent fat pads in human lower eyelids	OADSCs	20	In vitro	Regenerative potential declines with donor age	[29]
7	Influence of donor age on the differentiation and division capacity of human adipose-derived stem cells	ADSCs	18	In vitro	No significant correlation with age	[30]
8	Donor age negatively impacts adipose tissue-derived mesenchymal stem cell expansion and differentiation	ADSCs	40	In vitro	Minimal effect on chondrogenic/osteogenic potential	[1]
9	The effect of age on the regenerative potential of human eyelid adipose-derived stem cells	OADSCs	13	In vitro	Aging reduced osteogenic, chondrogenic, and wound-healing abilities	[31]
10	The influence of aging on the regenerative potential of human adipose derived mesenchymal stem cells	ADSCs	28	In vitro	Older ADSCs had reduced proliferation and differentiation	[32]
11	Adipose-derived mesenchymal stem cells from the elderly exhibit decreased migration and differentiation abilities with senescent properties	Subcutaneous ADSCs	24	In vitro	Elderly ADSCs had reduced migration and higher senescence	[33]
12	Human periosteal derived stem cell potential: The impact of age	Periosteal stem cells	8	In vitro	Aging altered markers and bone remodeling gene	[34]
13	Phenotype, donor age and gender affect function of human bone marrow-derived mesenchymal stromal cells	BM-MSCs	53	In vitro	No correlation with donor age	[35]
14	Aging alters tissue resident mesenchymal stem cell properties	ADSCs	40	In vitro	Aging reduced differentiation ability	[36]

ADSCs: Adipose-derived stromal cells; 3D: Three-dimensional; OADSCs: Orbital adipose-derived stromal cells; BM-MSCs: Bone marrow-derived mesenchymal stem cells.

Table 4 Comparison of emerging strategies to augment regenerative potential of stem cells in the elderly

Strategy	Efficacy	Practicality	Cost-effectiveness	Major bottlenecks
HPC	Effective for rejuvenating stem cells by mimicking natural hypoxic environments, improving mitochondrial efficiency and reducing ROS accumulation	Relatively simple to implement in vitro but translating to in vivo conditions is challenging due to varying oxygen tensions	Low cost for in vitro applications; however, in vivo translation may incur higher costs	Difficulty in replicating in vivo oxygen conditions; risk of increasing genomic instability or harmful factor secretion in aged cells
Genetic modification (CRISPR/Cas9)	Highly effective in precisely editing genes associated with aging and cellular senescence, improving stem cell function	Technically challenging; requires specialized expertise and equipment	High initial cost for setup, but cost-effective for large-scale genetic modifications	Off-target effects; potential risk of inducing tumorigenesis or mutations in aged stem cells
Growth factor supplementation	Effective for enhancing cell survival, proliferation, and differentiation, especially in aged cells	Easy to apply, but requires careful management of dosages and delivery systems	Moderate to high cost depending on the growth factor and delivery system used	Short half-life of growth factors limits their long-term effectiveness; managing consistent delivery in vivo is challenging
Bioactive compounds	Promising for enhancing stem cell function through modulation of pathways like oxidative stress and mitochondrial function	Non-invasive and easy to implement, but requires high doses for efficacy	Relatively low cost for sourcing and application, though clinical use may require further investment	High doses required for efficacy, potentially leading to toxicity in elderly patients
Hybrid stem cell therapy	Effective for combining the strengths of different stem cell types (e.g., iPSCs for differentiation and MSCs for paracrine support)	Complex to implement and requires co-transplantation of different stem cell types or integration with biomaterials	High cost due to the need for multiple stem cell types and specialized biomaterials	Ensuring the stability and functionality of hybrid stem cell constructs; maintaining consistent results across heterogeneous cell populations
MSC-derived exosomes	Promising in promoting tissue repair and anti-inflammatory responses without the need for live-cell transplantation	Easy to apply in comparison to cell transplantation, but large-scale production and purification can be challenging	Moderate cost, but cell-free nature could reduce long-term treatment costs	Production scalability; ensuring exosome consistency across populations; unknown long-term effects
Activation of developmental signaling pathways	Effective for rejuvenating stem cells and restoring their regenerative potential by reactivating pathways like Wnt, Notch, Hedgehog, and PI3K/Akt	Technically feasible but requires precise control over pathway activation to avoid undesired effects like tumorigenesis	High cost due to the need for specialized reagents and tools for pathway modulation	Excessive or uncontrolled activation of pathways could lead to unwanted effects such as tumorigenesis; requires precise control
3D culture systems	Effective for improving stem cell behavior by providing a more physiologically relevant environment than traditional 2D cultures	Complex and requires specialized equipment and expertise	High initial cost for 3D culture systems, but cost-effective in the long term for large-scale research	Difficulty in translating results from 3D culture systems to in vivo applications; complexity of culture systems
Epigenetic rejuvenation	Effective for resetting the epigenetic clock and restoring stem cell function, particularly through small molecules and histone modifications	Relatively easy to implement, though the long-term effects of epigenetic modulation are not fully understood	Moderate cost for small molecules and inhibitors	Risk of inducing oncogenes or pluripotency; difficulty in achieving precise epigenetic control, especially in heterogeneous cell populations

HPC: Hypoxic preconditioning; ROS: Reactive oxygen species; MSC: Mesenchymal stem cell; iPSCs: Induced pluripotent stem cells; 3D: Three-dimensional; PI3K: Phosphatidylinositol 3-kinase; Akt: Protein kinase B.