番茄社区

Injecting old mice with blood from younger mice improved their cognitive abilities along with promoting new neuron growth in their spinal cords, researchers found -- further evidence that some factor in blood keeps regenerative processes going for a time, but then disappears with aging.

Two other studies by a different research group, published online in to coincide with the blood-transfusion study's appearance in , suggest that the mysterious factor could be growth differentiation factor 11 (GDF11), which previously was found to rejuvenate cardiac function in aged mice with heart failure.

These findings in turn build upon -- some by the same group at the University of California San Francisco (UCSF) and Stanford University in Stanford, Calif., responsible for the new Nature Medicine paper -- involving "heterochronic parabiosis," which connects the vascular systems of young and old mice so that the young animals' blood circulates through the older animals.

That research had also demonstrated a systemic rejuvenation effect. However, it is still not certain whether GDF11 is the factor underlying these findings.

The Boston-based group behind the Science papers, led by , and , at the Harvard Stem Cell Institute, found that injections of recombinant GDF11 increased skeletal muscle growth and neurogenesis, but did not test for effects on cognition. They did, however, examine olfactory function and skeletal muscle strength and endurance.

These findings are likely to attract considerable attention, not only in the consumer press, but also from researchers seeking to discover the mechanisms of senescence and those looking for treatments for diseases of aging.

Young Blood Abates Cognitive Aging in Older Mice

In the Nature Medicine paper, researchers led by and Stanford's told how they extended their parabiosis work.

Gene expression profiling of animals used in these experiments showed that pathways related to hippocampal plasticity, such as those regulated by the cAMP response element binding protein (Creb), were differentially activated in the older mice when they were infused with blood from young mice versus from other old mice.

The researchers focused on the hippocampus because it is the seat of memory formation and is especially prone to atrophy with aging.

Additional experiments showed that Creb phosphorylation was definitely among the elements that were differentially affected in the parabiosis studies. In vitro studies of hippocampal neurons indicated that long-term potentiation was enhanced via the young-blood exposure in the older animals.

Those findings led the California group to try a simpler blood-transfer experiment. They simply injected older mice (18-months-old) with 0.1 mL of plasma from 3-month old mice eight times over a 3-week span, and then performed several cognitive tests.

The animals showed marked improvements in performance relative to untreated mice of the same age. When older animals were injected with heat-denatured plasma from young mice, however, "the beneficial effects of young plasma were mitigated," the researchers wrote.

Villeda, Wyss-Coray, and colleagues concluded that some heat-labile factors were responsible for rejuvenating cognitive function in the older mice.

The researchers also further established a key role for Creb in mediating these effects. In mice whose Creb signaling activity was artificially silenced, heterochronic parabiosis failed to boost their dendritic spine density, whereas this parameter was significantly increased with parabiosis in Creb-normal older mice.

Silencing Creb activity also reduced -- though it didn't completely eliminate -- the cognitive rejuvenation after injecting the animals with plasma from young mice.

All in all, "these behavioral data indicate that cognitive improvements observed in aged animals after systemic administration with young plasma are mediated in part by Creb," the researchers wrote.

GDF11 and Neurogenesis

Rubin, Wagers, and colleagues cited the earlier work by Villeda and colleagues as part of their rationale for believing the blood contains some type of rejuvenating factor, which they thought could be GDF11. In the work published last year, they found that GDF11 reversed the cardiac hypertrophy seen in older mice with heart failure.

Their work and that of others had shown that GDF11 levels decline with age, which bolstered it as a candidate rejuvenating factor.

In the new studies, the Boston researchers used their own heterochronic parabiosis model, as well as injection of recombinant GDF11, to identify its effects on nervous system tissue and also the vasculature (another system that loses plasticity and regenerative capacity with age).

"Our experiments reveal a remodeling of the aged cerebral vasculature in response to young systemic factors, producing noticeably greater blood flow," they reported.

In addition, the researchers observed neural stem-cell proliferation in the subventricular zone and olfactory neuron growth.

The same effects were seen when, instead, the group injected GDF11 protein into the aged mice.

The researchers did perform a functional analysis to examine whether the olfactory neurogenesis affected the animals' sense of smell. Indeed, the treated older animals appeared to be more sensitive to odors -- for example, spending the same amount of time exploring areas with low concentrations of odorants as did young mice, which was significantly longer than untreated older mice.

However, the nature of the experiments left the researchers uncertain as to whether the increased neurogenesis was a direct result of GDF11 action, or whether it was secondary to the improved blood flow.

In another potentially significant finding, the group found that putting blood from old mice into young mice had different effects depending on just how old the old mice were.

When they used blood from 15-month-old mice, little to no change was seen in the younger animals. But when blood from 21-month-old mice was inserted into young mice, the researchers saw a "dramatic" decrease in neural stem-cell populations, suggesting that the relevant factor in young blood not only vanishes with age, but is necessary to maintain these cell populations during youth.

GDF11 and Skeletal Muscle

Another Harvard group led by Wagers and Lee also looked at the effects of GDF11 on skeletal muscle in old mice, reporting the results in a separate Science paper.

A 2005 study had shown that heterochronic parabiosis in mice reversed the decreases in skeletal muscle strength and endurance typically seen with aging. The new studies with recombinant GDF11 were intended to confirm the Boston group's hunch that this protein is responsible for the effect.

Young mice injected with the protein showed no differences from controls, but aged mice had increased numbers of satellite cells with intact DNA as well as a 75% reduction in the number of satellite cells with severely damaged DNA (another common finding in older mice).

The GDF11-treated old mice also recovered faster from injury compared with sham-treated controls. Tests of grip strength and their endurance on an exercise wheel showed increases relative to controls.

No specific role for Creb signaling was mentioned in either Science paper. Instead, the researchers' mechanistic investigation centered on the PPAR-gamma coactivator 1a, which they described as "a master regulator of mitochondrial biogenesis." They also reported increased basal levels of autophagosome markers.

"Collectively, these data suggest enhanced autophagy/mitophagy and mitochondrial biogenesis as likely explanations for the cellular remodeling of muscle fibers in rGDF11-treated aged mice," they wrote.

Needless to say, a clinical trial of GDF11 would be watched very closely, but the Harvard group made no mention of imminent plans for one.