We believe that one of the hallmarks of aging is the decline of function in adult stem cells. So far it was more or less well-studied only in the hematopoietic system. Researchers explain this phenomenon by a mechanism where gene expression changes during the aging process. But what do we know about other adult stem cells in our body? Are there any parallels between aging of the hematopoietic system and other tissues? Now Sean Morrison’s team, based in U of Michigan (Ann Arbor) provide us a new insight to this problem.
To remind you what’s going on in hematopoietic system I’d cite exellent picture from the commentary to last year work of Morrison’s lab. They figured out a new precise transcription factor- Sox17, switching from high to low level after birth of mice.
This picture demonstrates transcriptional regulation of hematopoietic stem cells during mouse development (credit: Jang Y-Y and Sharkis SJ, 2007):
Let’s get back to parallels in the adult stem cell system. The first gene discovered to play a role in stem cell self-renewal and aging in both hematopoietic and neural systems was Bmi-1. Now, Morisson decided to dig deeper and find new players in aging of neural as well as hematopoietic stem cells.
A full-genome screen in blood cells showed that Hmga-2, a small chromatin-associated protein, was the only protein that was highly expressed in HSCs compared to other blood cells and whose expression was lower in old adult mice than in young adult mice. Further investigation found a similar age-related expression pattern in neural stem cells.
Furthermore Morrison’s guys connect famous Bmi-1 (which repress the expression of Ink4a/Arf genes) with newly discovered Hmga-2:
“As Hmga2 is turned off in ageing stem cells by increasing let-7b expression, this allows Ink4a and Arf to be expressed,” explains Morrison. “The take-home message of the paper is that we have identified an entire pathway of genes that change in expression with age in stem cells.”
Relative expression changes of Let7b, Hmga2, Ink4a and Arf during aging
(credit: Tzatsos A and Bardeesy N, 2008):
Now, let’s get close to cancer. Bmi-1 is known as a tumor promotor, and genes that it repress – Ink4a/Arf are tumor suppressors. Hmga2 is anti-aging, but is a tumor promotor. So, aging of adult stem cell system actually protects us from cancer.
I was thinking – we already know so many molecular players in the aged stem cell and we’ll get to know even more in the next few years, and connect them to the network and draw parallels, but so what? One new gene = Cell or Nature paper – that’s good for scientists, but how can we apply our knowledge?
Well, the most interesting part is that if we can inhibit these 2 guys – Ink4a/Arf in a very specific way, we can increase tissues regeneration (by increasing stem cell self-renewal). Yea, we really need it when we get injured.
Fans of anti-aging therapy hope that in the future we can inject small molecules which regulate genes expression and play with longevity. But if you will miscalculate a dosage, just for a little bit, you know what you will get – cancer!