Zhang et al recently published a paper in Nature – let’s break it down to see what it means!
- cells expressing two genes decrease with age in the hypothalamus
- if you knockout cells expressing those genes you get bad impacts on lifespan and fitness
- if you put neural stem cells into the hypothalamus, mice live longer and are healthier
- maybe this works through exosomes containing miRNA
Can the brain alone control lifespan?
First, it’s good to realize that there’s a history here. There are lots of interesting papers out there claiming to show that doing things just to the brain can increase the lifespan of a mouse. For example, knocking out specific genes in the brain (IGF-1R)  or increasing them (SIRT1) , or even just increasing the temperature of the hypothalamus  can make mice live longer.
So what does this paper show?
We lose neural stem cells (NSCs) with age
The above (from Figure 1a) shows that two genes ‘characteristic’ of neural stem cells – Sox2 and Bmi1 – are much less strongly expressed in old (22M = 22 months) vs young (2M = 2 months) mice.
Killing cells expressing Sox2 had bad effects on endurance and behavior
Removing ~70% of the cells expressing Sox2 (they did this with a lentivirus – injected into the part of the hypothalamus they thought would be sensitive to loss of these cells – which expressed a protein under the promoter of Sox2, which turns a drug they gave into a toxin). These are the mice in red above – as you can see, they consistently do worse across a variety of tests (from muscle endurance to novel object recognition).
Killing cells expressing Sox2 in part of the mouse hypothalamus led to decreased lifespan
The group took old mice (15 months), and repeated what they did with Sox2, but this time putting the protein under the expressing of Bmi1 and knocking out these cells in a specific part of the hypothalamus. They saw similar bad effects on endurance and cognitive function to what they did with Sox2. They then tried knocking out the Sox2+ cells in 8-month-old mice and saw a decrease in lifespan (shown above, treated mice in red).
Injecting modified NSC cells into the hypothalamus increased lifespan
The group took htNSC (hypothalamic neural stem cells) from newborn mice and modified them to express a gene which would help them resist an inflammation response. They then put these in hypothalamus of middle-aged mice, and saw improvements in locomotion and cognitive function. Putting these into the hypothalamus of 18-month old mice resulted in the lifespan increase seen above.
Treating middle-aged mice with just the exosomes secreted by hypothalamic neural stem cells was possibly good for endurance and cognition
This is where the part of the paper to focus on comes in – if the group knocked out the neural stem cells in the brain, as they had previously, treating those mice with just exosomes from the stem cells seemed to restore cognition and endurance. They then showed that taking 16-month-old mice that were normally aged, and injecting their hypothalamus with exosomes 3x / week, for 4 months, resulted in preventing some normal declines seen with aging (light blue is normal mice after 4 months, strong blue is mice injected with exosomes). The results seem positive, but require some following up.
- The study was done in C57BL/6 mice, which are just pretty weird from a physiology perspective. Everyone uses them, so it’s an extremely common problem – just one it’s worth not forgetting.
- We probably need some really rigorous follow up on the exosomes impacting physiology (for example, if they lead to a substantial increase in lifespan, particularly compared to control mice that don’t have things injected into their brain, I’d be excited).
- As the group mentions, what other things could these cells be doing or secreting that might impact aging? They mention neuropeptides, which we already know are super interesting in this regard.
Kappeler, L., De Magalhaes Filho, C., Dupont, J., Leneuve, P., Cervera, P., Périn, L., … Holzenberger, M. (2008). Brain IGF-1 receptors control mammalian growth and lifespan through a neuroendocrine mechanism. PLoS biology, 6(10), e254. doi:10.1371/journal.pbio.0060254
Satoh, A., Brace, C. S., Rensing, N., Cliften, P., Wozniak, D. F., Herzog, E. D., … Imai, S.-I. (2013). Sirt1 Extends Life Span and Delays Aging in Mice through the Regulation of Nk2 Homeobox 1 in the DMH and LH. Cell metabolism, 18(3), 416–30. doi:10.1016/j.cmet.2013.07.013
 Satoh, S., Series, R., Forbush, B., Mcgloin, M., Tyryshkin, a M., Dismukes, G. C., … Walker, L. M. (2006). Transgenic Mice with a Reduced Core Body Temperature Have an Increased Life Span. Nature, 314(November), 825–828. http://doi.org/10.1126/science.1132191