Fight Aging!

The protein growth differentiation factor 11 (GDF11) has been in the news over the past couple of years. In the course of conducting parabiosis research, in which the circulatory systems of old and young mice are linked, researchers established that levels of GDF11 decline with age in that species. Restoring youthful levels of GDF11 has been shown in some studies to improve numerous measures of age-related decline, perhaps largely through signaling that instructs stem cells to increase their tissue maintenance activities. Not all of the evidence is positive, however. There is an ongoing debate over whether or not studies were correctly interpreted, as GDF11 is similar enough to myostatin to confound some tools, a range of other objections and opposing evidence, and a first pass at obtaining human data suggests that GDF11 doesn't decline with age in our species in the way it does in old mice.

Does raising the level of GDF11 in humans have any sort of future as the basis for a therapy? In theory anything that can put stem cells back to work, reversing some of the characteristic age-related decline in stem cell function, is worth chasing to the same extent that stem cell therapies are worth chasing. The likely best outcomes are in the same ballpark, and work through similar mechanisms. This doesn't fix any of a range of important cell and tissue damage that causes age-related disease, but benefits are benefits. The question is whether or not GDF11 research is on the right track. At this point the balance of evidence for and against, coupled with questions about the methodology in some of the studies, suggests it is too early to tell - and at the very least there are a number of points that need clarification.

The study linked below falls on the negative side of the fence, showing no benefit to life span resulting from increased levels of GDF11 in a lineage of mice engineered to suffer accelerated aging. Evaluating results in accelerated aging models is a challenge, however. It all depends on the fine details of what exactly is involved in that accelerated aging - which is never actually accelerated aging, but rather some form of runaway biological damage that doesn't play a significant role in normal aging. That is good enough for some investigations, in which the precise nature of the damage isn't all that important, because the age-related condition of interest is very similar despite the very different nature of the low-level cell and tissue damage. Still, it has to be said that for every study in which the use of an accelerated aging lineage produced clear and unambiguously useful results, as was the case for senescent cell clearance back in 2011, there are half a dozen more in which the waters remain muddy. The researchers are trying hard to prove relevance in this paper, but I have to say that it still looks pretty muddy to me; there are any number of ways we might connect the particular approach to accelerated aging and GDF11 activities.

GDF11 administration does not extend lifespan in a mouse model of premature aging

The existence of "rejuvenating" factors in young blood capable of improving the function of aging stem cells was first demonstrated in 2005. A decade after this seminal contribution, the new wave of studies has been on the search for those circulating regulatory molecules that can restore the regenerative function of old stem cells and reverse aging. Among several cell-extrinsic factors and metabolites identified to date, GDF11 has been found to be one of the most powerful anti-aging candidates. Thus, it has been shown that GDF11 levels in blood decline with age, and that its supplementation to reach young physiological range in old mice improved the features and function of a number of age-deteriorated tissues, including heart, skeletal muscle and brain. However, recent reports have shown contradictory data questioning the capacity of GDF11 to reverse age-related tissue dysfunction. The availability of the Zmpste24-/- mouse model of accelerated aging, which shares most of the features occurring in physiological aging, gives us an excellent opportunity to test in vivo therapies aimed at extending lifespan both in pathological and normal aging. On this basis, we wondered whether the proposed anti-aging functions of GDF11 would have an overall effect on longevity.

We first determined whether GDF11 levels decline in our mouse model of premature aging in the same manner as it has been reported in physiological aging. We performed western-blot analyses with plasma samples obtained from the same wild-type and Zmpste24-/- mice at the age of 1.5 months and 3 months, to monitor a possible decline over time, considering that average lifespan of these mutant mice is 4 months and that accelerated aging symptoms start to manifest around the age of 2 months. We used the same commercial antibody as the one previously reported in the original study in which GDF11 was first identified as an anti-aging factor. We observed a marked decrease in GDF11 plasma levels in Zmpste24-/- mice compared with wild-type littermates at the age of 3 months.

To test our hypothesis about a possible role for GDF11 on lifespan extension, we did use the same commercial recombinant GDF11 (rGDF11) protein that has been used in those studies describing its anti-aging properties, and at a dosage capable of raising its levels in Zmpste24-/- plasma samples. However, rGDF11 daily treatment did not extend the lifespan of progeroid mice compared with vehicle-treated Zmpste24-/- littermates. It has been suggested that some of the original conclusions about GDF11 cardioprotective effects could be due to the decrease in body weight observed as a secondary effect of rGDF11 daily administration. Our results showed that rGDF11 treatment only caused a slightly reduction in the body weight of female Zmpste24-/- mice compared with vehicle-treated littermates during the first days of the experiment, whereas no significant differences were observed in the male cohort. In conclusion, our results demonstrate that circulating GDF11 levels are reduced in our mouse model of premature aging, which shares most of the symptoms that occur in normal aging. However, GDF11 protein administration is not sufficient to extend longevity in these progeroid mice. Although accelerated-aging mouse models can serve as powerful tools to test and develop anti-aging therapies common to both physiological and pathological aging, the existence of certain differences between the two processes implies that further investigation is still required to determine whether long-term GDF11 administration has a pro-survival effect on normal aged animals.