The Biochemistry of GDF11 is Complex, and Whether or Not it Has a Significant Role in Aging Remains a "Matter of Lively Debate"

Work on GDF11 is one of a number of examples that illustrate why one should always wait a year or two before becoming too excited about a novel line of research into mechanisms of aging or potential treatments for aging. Investigation of GDF11 grew out of heterochronic parabiosis studies, in which the circulatory systems of old and young mice are linked. The old mice show benefits, and the early theories as to why this is the case focused on the possibility of beneficial factors in young blood. GDF11 was identified as one candidate. The initial research results in 2013 and 2014 garnered considerable attention, and suggested that a straightforward increase in circulating levels of GDF11 could improve stem cell function and a range of other measures of decline in old mice.

In the few years since then, however, these results have been challenged on a number of fronts. Firstly as to whether or not assays were actually correctly measuring GDF11 levels versus levels of the very similar protein myostatin. Despite their similarities the two have very different functions. Replication has also been an issue. Researchers have shown, for example, that GDF11 appears not to decline with age in humans, unlike the conclusions drawn from the earlier mouse studies. Further, administration of GDF11 doesn't extend life in the progeroid mouse models that are widely used as a testbed to obtain faster data for therapies that might adjust the pace of aging. Additionally, the hypothesis that the benefits of parabiosis arise from factors in young blood is looking somewhat weak these days, given the more recent production of compelling evidence to suggest that it is more a matter of dilution of harmful factors in old blood.

As a final nail, and as illustrated by the paper below, the biochemistry of GDF11 in mice appears to be significantly more nuanced than a simple decline with age - given better assays and measures in different tissues, levels of GDF11 seem to do just about everything except the expected, and there is little of the earlier understanding to be found in the later, better data. This is definitely a part of the field where observers should step back for a few more years, let researchers sort out the contradictions, and then see if there is anything of interest left over at the end of the day.

Modulation of GDF11 expression and synaptic plasticity by age and training

The growth differentiation factor 11 (GDF11) is a member of the transforming growth factor β (TGFβ) superfamily, homologous to another muscle-derived hormone, myostatin (MSTN). Although GDF11 and MSTN share 89% amino acid sequence identity within the C-terminal region, these proteins may have different functions. MSTN is expressed predominantly in skeletal muscle and plays an evolutionarily conserved role in antagonizing postnatal muscle growth. In fact, disruption of MSTN in many mammals (e.g. mice or cattle) causes muscle hypertrophy. In contrast, GDF11's functions in postnatal tissues are less known because of perinatal mortality of GDF11 knockout animals. Nevertheless, various works have suggested a broader role of GDF11 in mammalian development and identified GDF11 as a hormonal regulator of different organs including brain and skeletal muscle. More recently it has been reported that overexpression of GDF11 in mice results in substantial atrophy of skeletal and cardiac muscle, inducing a cachexic phenotype not seen in mice expressing similar levels of MSTN.

Recently, studies have focused on the search for regulatory molecules that can reverse aging. Among these factors, GDF11 has been identified as a potential anti-aging candidate. However, some data on GDF11 expression and function are contradictory and GDF11 role in aging is still matter of lively debate. Indeed, initial studies in rodent models exploiting heterochronic parabiosis (in which circulatory systems of young and aged animals are connected) or using recombinant protein treatment, identified GDF11 as a molecule capable of rejuvenating cerebral, cardiac, skeletal muscle functions and attributed the diminished regenerative capacity of skeletal or cardiac muscle and brain of old mice to the decrease of GDF11 serum levels. Afterwards, other reports questioned the age-related decline of circulating GDF11 and showed that GDF11 increases with age causing inhibition of muscle regeneration rather than fostering rejuvenation. In addition, the specificity of antibodies and the methods used to detect the protein in previous studies have been criticized. Therefore, further studies are needed to evaluate whether young and old individuals have a different GDF11 protein expression in tissues (e.g., skeletal muscle, hippocampus), and to clarify the actual role of GDF11 in the regulation of rejuvenation processes and longevity.

The increase of physical activity has been proposed as an effective therapeutic strategy to reduce the age-derived decline of muscular and cognitive functions although most of the molecular mechanisms underlying the benefit of exercise are still unknown. During the aging process exercise mediates beneficial effects on several brain functions by activating neurogenesis and delaying neurodegenerative processes. Recently, it has been reported that exercise mediates beneficial effects on brain plasticity and functions. Brain plasticity refers to the ability of the brain to modify its structure and function in response to maturation, learning, environmental stimuli, or pathological state. This activity-dependent phenomenon translates into a persistent boost in synaptic transmission, called long-term potentiation (LTP) that is considered the cellular and molecular substrate of learning and memory processes. Aging is a biological process associated with physiological cognitive decline; in particular, it can harm quality of life and result in deficits of declarative and working memory, spatial learning, and attention. Heterochronic parabiosis of young blood in old mice has been shown to enhance LTP and this effect has been attributed to the high GDF11 levels present in the blood of young mice.

The present study is an attempt to clarify, in a murine model, whether GDF11 expression in skeletal muscle and hippocampal tissues undergoes modulation during the aging process and whether training modulates GDF11 expression and LTP. Nowadays, it is still controversial whether tissue levels of GDF11 protein expression are age-related. In the current study we provide evidence, by using an antibody which specifically recognizes GDF11 and does not cross react with MSTN, that this protein is expressed at higher levels in the skeletal muscle tissue of old mice compared to young animals independently of sex and strain. The results were also confirmed by quantitative analysis of GDF11 mRNA. This observation is in sharp contrast with studies showing GDF11 decline in skeletal muscle with age, but in agreement with other studies in which GDF11 protein expression was found to increase with age.

The controversial results may reflect differences in experimental designs, strategies, detection reagents, specificity of GDF11 antibodies, sources of recombinant proteins used as controls. Our results, obtained with qRT-PCR using specific primers mapping in a GDF11 region which does not overlap with MSNT sequences and immunoblot analysis using an antibody specifically recognizing recombinant GDF11, indicate that skeletal muscles of old mice express higher GDF11 levels than young mice. The latter findings discourage the use of recombinant GDF11 to counteract age-related cardiac and skeletal muscle decline.

The age-dependent increase of GDF11 observed is limited to skeletal muscle; in fact, a wide variation of GDF11 protein expression was detected in the hippocampi of old animals. Actually, also in other tissues and in the serum the relationship between expression level and function of GDF11 is quite controversial. Recently GDF11 was reported to increase neurogenesis and to be involved in brain rejuvenation of aged mice. In the present study, we found variable levels of GDF11 in hippocampi of old mice with respect to those detected in young mice. Moreover, the GDF11 expression found in the hippocampi did not correlate with the impairment of synaptic plasticity in the hippocampal CA1 region, measured by LTP assay in old mice.

Physical exercise has been proposed as an effective strategy to reduce the detrimental influence of aging on muscle and cognitive function. We sought to investigate whether the beneficial effects of a forced long-term specific training program (i.e., continuous progressive protocol, which can be appropriate also for aged animals) may result in modulation of GDF11 expression. In our model, training slightly but significantly increased GDF11 levels in skeletal muscles of young animals, but it did not affect protein expression in the same tissues of old mice. In hippocampal tissues training did not substantially affect GDF11 protein levels of young mice, whereas it significantly decreased GDF11 protein expression in old mice. Based on these results, the beneficial effects of training on synaptic plasticity did not consistently correlate with modifications of GDF11 expression in hippocampi.

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