Researchers from AgeX Therapeutics and other organizations have proved the feasibility of reprogramming banked cells derived from a supercentenarian. Their discovery portends exciting new possibilities for aging research.
What is cellular reprogramming?
Cellular reprogramming is the process of reverting mature, specialized cells into induced pluripotent stem cells (iPSCs), which can develop into any cell type found in the human body. Cellular reprogramming technology was pioneered in 2006 by Drs. Takahashi and Yamanaka, who achieved this impressive result by overexpressing just four genes, Oct4, Sox2, Klf4, and c-Myc (OSKM), which became collectively known as the Yamanaka factors. For this breakthrough, Yamanaka was awarded the Nobel Prize in 2012. Fun fact: Yamanaka called these cells iPSCs – with a small “i” – as a nod to the iPod and similarly named devices.
No upper age limit on reprogramming
AgeX Therapeutics was founded by Dr. Michael West, a true pioneer of longevity research who founded his first company in the field, Geron Corporation, in 1990. We interviewed Dr. West at last year’s Ending Age-Related Diseases conference, which we will be holding this year as well.
This research [1] was conducted with cells derived from a single 114-year-old female. People near her age are extremely rare: only 0.15% to 0.25% of centenarians (100 years or older) become supercentenarians (110 years or older). Supercentenarians exhibit even greater resistance to age-related degenerative diseases than centenarians; therefore, they have an extreme “compression of morbidity” – an especially long healthspan followed by a rapid decline into death. Scientists reasonably believe that centenarians’ and supercentenarians’ enviable health can be at least in part attributed to their genomic and epigenomic characteristics, which makes them highly valuable subjects for longevity research.
The researchers used banked lymphoblastoid cell lines (LCLs), which are a popular source of cells for reprogramming and other areas of cellular research. LCLs are a derivative of B lymphocytes that have been immortalized (conditioned for continuous reproduction). This technology provides a virtually endless supply of person-specific cells.
LCLs, taken from this 114-year-old supercentenarian (SC), a 43-year-old healthy disease-free control (HDC), and an 8-year-old with a rapid aging disease (Hutchinson-Gilford progeria syndrome, HGPS) were then reprogrammed to give rise to iPSCs. The researchers report not detecting any negative impact of extreme donor age on their ability to obtain iPSC clones. One substantial difference did arise: in iPSCs derived from all three donors, telomere length, which declines with age (or as a result of progeria) was completely reset to nearly embryonic levels. While virtually all HDC-iPSCs and HGPS-iPSCs exhibited this effect, telomere length regeneration only occurred in 1 in every 3 SC-iPSCs. This shows that extreme age still poses some limitations on successful cell regeneration. The process of telomere resetting is not entirely understood, and even less is known about the factors behind impaired telomere resetting in extremely old people. The researchers suggest that it might be the “epigenetic memory” of old cells that affects the reset of telomere length.
The next step was to determine whether the newly-obtained pluripotent stem cells could be differentiated into mesenchymal progenitor cells (MPCs), which are themselves multipotent (but not pluripotent), as they are able to differentiate further into one of the several types of cells belonging to our skeletal tissues, such as cartilage, bone and fat. MPCs, being more specialized cells, exhibited donor-dependent differences in gene expression. The HDC-MPCs and the SC-MPCs were more closely related to each other than to the HGPS-MPCs, which exhibited overexpression of genes commonly associated with aging. In short, the genetic causes of early aging had survived the reprogramming, which may limit this technology’s prospects of curing progeria. Yet another interesting finding was that many genes that were differentially expressed in SC-MPC compared to HDC-MPCs are known to play a role in glucose metabolism and fat regulation. These genes, the researchers suggest, mimic caloric restriction. It may be possible to harness these genetic and epigenetic mechanisms for use in longevity therapies.
Conclusion
In this study, the scientists tried “to assess the upper limit for reprogramming and to potentially provide means of modelling extreme healthspan”. Although experiments with centenarians’ cells have been conducted before [2], this is the first time that supercentenarian-derived cells were used in a study of this kind. The scientists were able to prove that there is apparently no upper age limit for cellular reprogramming, even though telomere length recovery seems to be affected by age. This research suggests that even extremely aged people can potentially benefit from reprogramming therapies. It also offers new opportunities for studying supercentenarians’ remarkable healthspan in vitro.
Literature
[1] Lee, J., Bignone, P. A., Coles, L. S., Liu, Y., Snyder, E., & Larocca, D. (2020). Induced pluripotency and spontaneous reversal of cellular aging in supercentenarian donor cells. Biochemical and Biophysical Research Communications.
[2] Lapasset, L., Milhavet, O., Prieur, A., Besnard, E., Babled, A., Aït-Hamou, N., … & Lehmann, S. (2011). Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state. Genes & development, 25(21), 2248-2253.
