Anton Simeonov Ph.D. National Institute of Health

This literature review looks at two papers where researchers assess the rejuvenating qualities of a circulating protein.

A pair of publications in Science attempt to address the often-controversial topic of the rejuvenating, or regenerative, effects of tissues/fluids derived from young organisms on their older counterparts. Specifically, experiments in mice have shown that blood from young mice has a rejuvenating effect on older mice. The pair of studies tackle questions such as exactly which blood component is responsible for the rejuvenating effects and exactly what some of those rejuvenating effects are. Both studies identify the circulating protein growth differentiation factor 11 (GDF11), a member of the transforming growth factor-β (TGF-β) family, as being at least one of the agents responsible for the beneficial effects.

In the Katsimpardi article,* the team demonstrated that application of recombinant GDF11 protein (rGDF11), accomplished by injecting 22-month-old mice with rGDF11 for 4 weeks, promoted remodeling of the aged cerebral vasculature, leading to an improvement of blood flow, and activation of subventricular zone neural stem cell proliferation, which in turn resulted in an improved olfactory function (Figure 1).

Figure 1. GDF11 enhances vascular remodeling and neurogenesis. (A and B) Confocal images of coronal SVZ sections showing that 22-month-old mice injected with rGDF11 for 4 weeks have (A) enhanced vascularization as well as (B) increased Sox2+ neural stem cell populations compared with those of control. (C) Measurement of blood vessel volume in rGDF11-treated and control mice (n = 9). (D) Quantification of Sox2+ cells in the SVZ area (n = 6); “n” indicates the number of animals for each experimental group. (E) Quantification and (F) representative images of the percentage of phospho-SMAD2/3+ cells in primary brain capillary endothelial cell cultures treated with either GDF11 (40 ng/mL) or TFG-β (10 ng/mL) in the presence of sodium orthovanadate used to inhibit phosphatase activity for 30 min (n = 7). Scale bar, 100 μm. Data are shown as mean ± SEM; statistical analysis was performed with t test, between each experimental condition and the untreated control; *p < 0.05, **p < 0.01, ***p < 0.001.

Figure 1

In the Sinha study,** a similar treatment of aged mice with recombinant GDF11 resulted in improvements of myofibrillar and mitochondrial morphology, as revealed by electron microscopy, as well as improvements in muscle performance parameters (Figure 2).

Figure 2. Improved muscle physiology and physical function after rGDF11 supplementation. (A) Electron micrographs of transverse sections of TA muscle from vehicle- or rGDF11-treated aged mice (representative of n = 4 mice per group). Arrows indicate swollen mitochondria. (B and C) Western blot of PGC-1α (B) and LC3 forms I and II (C) in tibialis anterior (TA) muscle extracts from cardiotoxin-injured or uninjured vehicle- or rGDF11-treated aged mice. Three animals are shown for each experimental group. Densitometric quantification of Western data are provided below each blot, normalized to glyceraldehyde phosphate dehydrogenase (GAPDH) (B) or Actin (C). (D and E) Scatter plots of exercise endurance (D), maximum treadmill runtime in a 90-min window or forelimb grip strength (E) of vehicle- or rGDF11-treated aged mice. Grip strength is plotted as maximum force (Newton, N) exerted in triplicate trials. The red line represents the maximum grip strength of 33- to 39-week-old young male mice. Data are presented for individual mice (black symbols) overlaid with mean ± SD (orange lines). P values were calculated by Mann-Whitney analysis. n, number of mice used for each analysis.

Figure 2

While the exact mechanisms by which GDF11 causes “rejuvenation” of the circulatory and musculoskeletal system remain to be delineated, the present reports highlight the possibility of treating a range of genetic conditions, as well as diseases of “old age,” through GDF11 supplementation either via direct application of recombinant protein or by gene therapy means. 

*Abstract from Science 2014, Vol. 344: 630–634

In the adult central nervous system, the vasculature of the neurogenic niche regulates neural stem cell behavior by providing circulating and secreted factors. Age-related decline of neurogenesis and cognitive function is associated with reduced blood flow and decreased numbers of neural stem cells. Therefore, restoring the functionality of the niche should counteract some of the negative effects of aging. We show that factors found in young blood induce vascular remodeling, culminating in increased neurogenesis and improved olfactory discrimination in aging mice. Further, we show that GDF11 alone can improve the cerebral vasculature and enhance neurogenesis. The identification of factors that slow the age-dependent deterioration of the neurogenic niche in mice may constitute the basis for new methods of treating age-related neurodegenerative and neurovascular diseases.

**Abstract from Science 2014, Vol. 344: 649–652

Parabiosis experiments indicate that impaired regeneration in aged mice is reversible by exposure to a young circulation, suggesting that young blood contains humoral “rejuvenating” factors that can restore regenerative function. Here, we demonstrate that the circulating protein growth differentiation factor 11 (GDF11) is a rejuvenating factor for skeletal muscle. Supplementation of systemic GDF11 levels, which normally decline with age, by heterochronic parabiosis or systemic delivery of recombinant protein, reversed functional impairments and restored genomic integrity in aged muscle stem cells (satellite cells). Increased GDF11 levels in aged mice also improved muscle structural and functional features and increased strength and endurance exercise capacity. These data indicate that GDF11 systemically regulates muscle aging and may be therapeutically useful for reversing age-related skeletal muscle and stem cell dysfunction.

Anton Simeonov, Ph.D., works at the NIH.

ASSAY & Drug Development Technologies, published by Mary Ann Liebert, Inc., offers a unique combination of original research and reports on the techniques and tools being used in cutting-edge drug development. The journal includes a "Literature Search and Review" column that identifies published papers of note and discusses their importance. GEN presents here one article that was analyzed in the "Literature Search and Review" column that analyzes two papers published in Science: one titled "Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors" authored by Katsimpardi L, Litterman NK, Schein PA, Miller CM, Loffredo FS, Wojtkiewicz GR, Chen JW, Lee RT, Wagers AJ, and Rubin LL; and the other titled "Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle" authored by Sinha M, Jang YC, Oh J, Khong D, Wu EY, Manohar R, Miller C, Regalado SG, Loffredo FS, Pancoast JR, Hirshman MF, Lebowitz J, Shadrach JL, Cerletti M, Kim MJ, Serwold T, Goodyear LJ, Rosner B, Lee RT, and Wagers AJ.

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