Paper Alert: Do Blood-Borne Factors Control Brain Aging?
Today in Nature, researchers led by Tony Wyss-Coray at Stanford University, Palo Alto, California, confirm what has been playfully called the “vampire principle”: Young blood rejuvenates older mice, while old blood contains factors that age the brains of young mice, suppressing neurogenesis. First author Saul Villeda previously presented the bulk of these data at the 2009 Society for Neuroscience annual conference (see ARF related conference story).
Villeda and colleagues reached this conclusion via parabiosis experiments in which they sutured the abdominal lining of a young mouse to that of an older mouse. The capillary beds fused, allowing the mice to exchange blood for two months. While neurogenesis in the dentate gyrus dropped in young mice subjected to the procedure, neuron production boomed threefold in the old mice. The researchers traced the neuron bust in young mice to blood-borne factors from the older animals—in particular, the chemokine eotaxin (also known as CCL11), which plays a role in allergic responses. Plasma CCL11 increases with age in both mice and humans, the researchers found. Systemically injecting eotaxin alone into young mice inhibited neurogenesis, confirming its central role.
The paper correlates these neurogenesis effects to deficits in learning and memory. Young mice who received either old blood or systemic eotaxin injections showed less long-term potentiation in the dentate gyrus than normal young mice, and also learned poorly in the water maze and in fear conditioning tests. The learning problems matched those of young mice whose neural stem cells had been ablated by radiation, suggesting that the lack of new neurons might be to blame for memory problems. But exactly how eotaxin causes these deficits is unclear. One question is whether it can directly affect the brain, or whether it acts through other plasma factors. To get at this question, the researchers injected eotaxin directly into the dentate gyrus, and again saw a dampening of neurogenesis. Importantly, when the researchers also injected an eotaxin-neutralizing antibody, neurogenesis remained high. The results suggest that the factor might act directly in the brain.
In an accompanying editorial, Richard Ransohoff at the Cleveland Clinic, Ohio, notes these data suggest that “factors that alter neurogenesis, such as exercise or systemic inflammation, might act by modifying the abundance of signaling proteins in the blood plasma.” It is not clear if eotaxin acts directly on stem cells, Ransohoff points out, as its receptor, CCR3, is not typically found on stem and progenitor cells. Ransohoff speculates that eotaxin could be acting on microglia, which are known to dampen neurogenesis under some conditions, or it might be suppressing interleukin-4, which normally acts to restrain brain inflammation that might otherwise impair neurogenesis. Though the mechanisms remain to be determined, “the good news from this report is that neural stem cells in the aging brain do not undergo irreversible decline and can respond to a favourable environment,” Ransohoff wrote.—Madolyn Bowman Rogers
- Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, Stan TM, Fainberg N, Ding Z, Eggel A, Lucin KM, Czirr E, Park JS, Couillard-Després S, Aigner L, Li G, Peskind ER, Kaye JA, Quinn JF, Galasko DR, Xie XS, Rando TA, Wyss-Coray T. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature. 2011 Sep 1;477(7362):90-4. PubMed.
- Ransohoff RM. Ageing: Blood ties. Nature. 2011 Sep 1;477(7362):41-2. PubMed.
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Just an observation: My 86-year-old father with Alzheimer's onset in 2006 had a gastrointestinal bleed and received 11 units of packed cells. After the first six units, his short-term memory improved significantly. He was able to read news articles and explain them 30 minutes later. Remembered visitors and their conversations. Did not repeat himself or ask the same questions repeatedly. Now at three weeks out from the last transfusion and no active bleeding, the short-term memory has returned to baseline, i.e., very poor. Coincidence, maybe, but it was nice to have "real" Dad back for a while.
I'd like to see an ARF Webinar on this topic.
Eotaxin or CCL 11 is known to recruit eosinophiles. This is thought to indicate a relationship to allergic reactions. Eosinophilic bodies have been reported in Alzheimer's disease cortex on neuropathological exams. They have been described as homogeneous electron-dense bodies on electron microscopic examination (1).
Possibly, there is some type of allergic response, or eosinophiles are being recruited by CCL 11 with resulting adverse effects on the brain and the brain deterioration noted in Alzheimer's disease.
Inoue M, Yagishita S, Itoh Y, Koyano S, Amano N, Matsushita M. Eosinophilic bodies in the cerebral cortex of Alzheimer's disease cases. Acta Neuropathol. 1996 Dec;92(6):555-61. PubMed.
University of Wisconsin
This paper supports the reproductive-cell cycle theory of aging, which indicates that reproductive endocrine dyscrasia mediates aging in all tissues via altered cell cycle signaling (Bowen and Atwood, 2004; Atwood and Bowen, 2011). The blood-borne factors inducing brain aging may, in fact, be due to elevated concentrations of circulating gonadotropins and GnRH, and decreased concentrations of sex steroids and inhibin, in the aged post-reproductive mouse. This work is further supported by the finding that transplantation of young ovaries (two-month-old) into middle-aged (11-month-old) mice significantly increased longevity by re-establishing the hypothalamic-pituitary-gonadal axis. These data indicate that reproductive hormones are primarily responsible for aging. Supporting this, the major cytokines correlated with aging in the 2011 paper by Villeda et al.—CCL2, haptoglobulin, and eotaxin (CCL11)—are regulated by (Bouckaert et al., 1986; Dahm-Kähler et al., 2006), or correlated with (Kass et al., 2010) LH and FSH concentrations.
Bowen RL, Atwood CS. Living and dying for sex. A theory of aging based on the modulation of cell cycle signaling by reproductive hormones. Gerontology. 2004 Sep-Oct;50(5):265-90. PubMed.
Atwood CS, Bowen RL. The reproductive-cell cycle theory of aging: an update. Exp Gerontol. 2011 Feb-Mar;46(2-3):100-7. PubMed.
Bouckaert PX, Evers JL, Doesburg WH, Schellekens LA, Brombacher PH, Rolland R. Patterns of changes in proteins in the peritoneal fluid of women during the periovulatory phase of the menstrual cycle. J Reprod Fertil. 1986 Jul;77(2):329-36. PubMed.
Dahm-Kähler P, Runesson E, Lind AK, Brännström M. Monocyte chemotactic protein-1 in the follicle of the menstrual and IVF cycle. Mol Hum Reprod. 2006 Jan;12(1):1-6. PubMed.
Kåss AS, Lea TE, Torjesen PA, Gulseth HC, Førre ØT. The association of luteinizing hormone and follicle-stimulating hormone with cytokines and markers of disease activity in rheumatoid arthritis: a case-control study. Scand J Rheumatol. 2010 Mar;39(2):109-17. PubMed.View all comments by Craig Atwood
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