Researchers here demonstrate that comparatively simple regenerative cell therapies, of the sort presently widely used, in which stem cells are derived from adipose tissue, will tend to introduce senescent cells into the recipient in the case of older donors. Senescent cells are constantly created and destroyed in the body, but the processes of clearance decline with age, and these cells are harmful when they linger for the long term: their secreted signals cause chronic inflammation, while also contributing to tissue dysfunction in a number of other ways. The presence of senescent cells in older individuals is one of the contributing causes of degenerative aging, and adding more such cells is something to be avoided.
Adipose-derived mesenchymal stem cells (ADSCs) or "preadipocytes" have been increasingly suggested for use in regenerative medicine as a treatment for a wide range of diseases due to their multipotency and accessibility. Older adults represent most likely recipients of ADSC therapies given the high burden of diseases in this population. Since autologous ADSCs are preferred in the clinic, it is essential to understand age-related changes influencing these cells. Emerging evidence suggests that ADSCs from aged donors have reduced regenerative potential, leading to diminished therapeutic efficacy. However, it is unknown whether transplanting ADSCs from aged donors might cause unexpected or even harmful effects in recipients. This is especially important for older adults, since they tend to be more vulnerable and less resilient to such stresses.
To examine this, we isolated ADSCs from 12 young (6-7 months, referred to as young ADSCs) and 12 old (28-31 months, referred to as old ADSCs) C57BL/6 male mice. We transplanted ADSCs from young or old donors into syngeneic 20-month-old C57BL/6 male mice. Four to six weeks after transplantation, we tested maximal walking speed, grip strength, physical endurance, daily activity, food intake, and body weight change to assess overall physical function in recipients, based on criteria used in clinical practice. ADSCs from old donors significantly impaired walking speed, grip strength, endurance, and daily activity of older recipient mice after transplantation, compared with mice transplanted with the same number of ADSCs from young donors.
Using single-cell transcriptomic analysis, we identified a naturally occurring senescent cell-like population in ADSCs primarily from old donors that resembles in vitro-generated senescent cells with regard to a number of key pathways. Overall, these findings suggest that ADSCs from old donors can induce physical frailty, which is highly associated with morbidity and loss of independence. Our study potentially begins new avenues of research to discover whether pharmacological interventions, such as senolytic drugs or anti-inflammatory drugs, can prevent or reverse dysfunction caused by transplanting ADSCs or even organs from old donors and improve clinical outcomes of transplantation for older patients.