Rejuvenation: It’s in our blood

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It has been known for some time that blood from young mice can positively impact aged animals, while blood from old mice has the opposite effect. Recent studies report that rejuvenating effects of young blood extend to multiple tissues and have identified GDF11 and CCL11 as factors mediating these effects.

Parabiosis is a surgical technique that involves joining the circulatory system of two animals such that they continuously exchange blood and other circulating factors. About a decade ago, this method was used to test whether the age of one animal has effects on the health of its partner through heterochronic parabiosis, where a young mouse shares it circulatory system with an old mouse. Strikingly, muscle stem cells and liver cells from the young mouse functioned less well, while the same cells from the old mouse showed molecular and functional evidence for rejuvenation (Conboy et al., 2005). Since then, similar effects have been demonstrated in other tissues including spinal cord (Ruckh et al., 2012), heart (Loffredo et al., 2013), and brain (Villeda et al., 2011). Recently, this work has been extended by the finding that injecting plasma from young mice is sufficient to enhance cognitive function and synaptic plasticity in aged mice (Villeda et al., 2014), and the identification of two molecules as key mediators of the beneficial and negative consequences from heterochronic parabiosis (Figure 1), Growth Differentiation Factor 11 (GDF11) (Katsimpardi et al., 2014; Sinha et al., 2014) and C-C motif chemokine 11 (CCL11) (Villeda et al., 2011).

Figure 1. Opposing effects of heterochronic parabiosis in mice.

Heterochronic parabiosis, in which a young mouse and an aged mouse share circulatory systems, improves health of the aged mouse while having negative health consequences for the young mouse. GDF11 and CCL11 have recently been identified as two of the factors mediating these effects.

GDF11, a member of the TGF-β superfamily, declines in blood with age (Loffredo et al., 2013), and restoration of youthful levels of GDF11 is sufficient to enhance stem cell and tissue function in heart (Loffredo et al., 2013). In contrast, blood levels of CCL11 increase with age, and this increase appears to contribute to the decline in neurogenesis and function of neural stem cells in the hippocampus (Villeda et al., 2011). Now, two new studies have found that GDF11 also has beneficial effects on skeletal muscle, the sub-ventricular nuclei and the hippocampus. Supplementation with GDF11 alone restored skeletal muscle strength, physical endurance, and regeneration following injury in aged mice (Sinha et al., 2014). Similarly, old mice treated with GDF11 had improved olfactory perception, brain vascularization, and neural stem cell function, which could translate into increased protection of the nervous system against age related challenges (Katsimpardi et al., 2014). Conversely, injecting CCL11 impaired learning and memory in young mice, likely by reducing neurogenesis in the hippocampus (Villeda et al., 2011). A CCL11-neutralizing antibody abrogated the negative effects of CCL11 treatment in young mice, although it was not reported whether the CCL11-neutralizing antibody alone could improve function in aged mice.

Another recent study suggests that the fruit fly homolog of GDF11, myogliannin, is secreted by muscle to regulate aging in that organism (Demontis et al., 2014). Demontis and colleagues found that overexpression of the Mnt transcription factor specifically in muscle was sufficient to attenuate age-associated declines in climbing ability and extend lifespan. Interestingly, it also caused changes in nucleolar structure of both muscle and adipocyte cells, suggesting that muscle Mnt has both cell autonomous and cell non-autonomous effects. Myogliannin was identified as a secreted factor induced by Mnt that mediates these effects, and overexpression of myogliannin specifically in muscle extends lifespan. Although it remains unclear whether myogliannin functions similarly to GDF11 (myogliannin is also homologous to myostatin and appears to function in some ways similarly to myostatin), the observation that both myogliannin and GDF11 are secreted factors that modulate aging-related phenotypes in flies and mice is intriguing.

Recent advances in aging research have led to the identification of a small but growing number of interventions that enhance longevity and promote healthy aging. For example, dietary restriction or treatment with the mTOR inhibitor rapamycin have both been found to increase lifespan in yeast, nematodes, fruit flies, and mice. Such interventions, if they can be successfully translated to people, have the potential to dramatically impact human health by simultaneously delaying the onset and progression of multiple age-related disorders (Kaeberlein, 2013). As such, the discovery of systemic factors that appear to modulate aging, such as GDF11 and CCL11, has potentially profound therapeutic implications. If similar mechanisms occur in people, then providing elderly individuals with plasma from young individuals, or even more specifically with GDF11 or a CCL11-neutralizing antibody, may lead to improved function of multiple organ systems. Given that these approaches are essentially restoring levels of our bodies’ own molecules toward a more youthful state, they may prove less prone to side effects compared to pharmacological interventions that slow aging, such as rapamycin.

On the other hand, altering the abundance of specific molecules in the context of an aged system may have unanticipated effects that are different from the young state. In this regard, it is rather surprising that it hasn’t yet been reported whether longer-term heterochronic parabiosis, or more specific treatments in aged animals such as young plasma or GDF11, does in fact significantly improve healthspan or lifespan of mice. This is important, both for evaluating the effects of such interventions in the context of the aging animals, as well as for understanding whether there are any substantial negative side effects associated with such treatments.

A related question is whether continuous treatment is required to fully rejuvenate tissues of aged mice, or perhaps a transient exposure to these factors might be sufficient. For example, injecting young plasma into aged mice eight times over a period of twenty-four days resulted in significant improvements in hippocampal-dependent learning and memory immediately following treatment (Villeda et al., 2014), but it is unclear whether these benefits persist or are rapidly lost once treatment is stopped. Finally, it remains to be ascertained whether these systemic factors act within well-known aging pathways, such as mTOR and growth hormone/insulin-IGF-1 signaling, or if they are effectors of novel aging pathways. Indeed, the factors regulating the expression of GDF11 and CCL11, the tissues involved in their production, their mechanism(s) of action, and why their expression changes during aging remain to be determined.

These discoveries set the stage for interesting times, as many remaining questions begin to be answered and the translational potential is explored. It seems likely that GDF11 and CCL11 are only the first two in a series of circulating molecules that will be found to influence aging of different tissues. Whether these are the most important or most potent molecules remains to be seen. Future studies in this area will likely bring forth new and exciting knowledge about the dynamics of aging and novel approaches to regenerative medicine.