Francesco Loffredo

Growth Differentiation Factor 11 Is a Circulating Factor that Reverses Age-Related Cardiac Hypertrophy

The most common form of heart failure occurs with normal systolic function and often involves cardiac hypertrophy in the elderly. To clarify the biological mechanisms that drive cardiac hypertrophy in aging, we tested the influence of circulating factors using heterochronic parabiosis, a surgical technique in which joining of animals of different ages leads to a shared circulation. After 4 weeks of exposure to the circulation of young mice, cardiac hypertrophy in old mice dramatically regressed, accompanied by reduced cardiomyocyte size and molecular remodeling. Reversal of age-related hypertrophy was not attributable to hemodynamic or behavioral effects of parabiosis, implicating a blood-borne factor. Using modified aptamer-based proteomics, we identified the TGF-β superfamily member GDF11 as a circulating factor in young mice that declines with age. Treatment of old mice to restore GDF11 to youthful levels recapitulated the effects of parabiosis and reversed age-related hypertrophy, revealing a therapeutic opportunity for cardiac aging.

Restoring Systemic GDF11 Levels Reverses Age-Related Dysfunction in Mouse Skeletal Muscle

Help the Aged Muscle function declines with age, as does neurogenesis in certain brain regions. Two teams analyzed the effects of heterochronic parabiosis in mice. Sinha et al. (p. 649) found that when an aged mouse shares a circulatory system with a youthful mouse, the aged mouse sees improved muscle function, and Katsimpardi et al. (p. 630) observed increased generation of olfactory neurons. In both cases, Growth Differentiation Factor 11 appeared to be one of the key components of the young blood. A circulating growth factor promotes youthful muscles and brains in aged mice. 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.

Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors

Help the Aged Muscle function declines with age, as does neurogenesis in certain brain regions. Two teams analyzed the effects of heterochronic parabiosis in mice. Sinha et al. (p. 649) found that when an aged mouse shares a circulatory system with a youthful mouse, the aged mouse sees improved muscle function, and Katsimpardi et al. (p. 630) observed increased generation of olfactory neurons. In both cases, Growth Differentiation Factor 11 appeared to be one of the key components of the young blood. A circulating growth factor promotes youthful muscles and brains in aged mice. 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.

Heart Failure With Preserved Ejection Fraction Molecular Pathways of the Aging Myocardium

Age-related diastolic dysfunction is a major factor in the epidemic of heart failure. In patients hospitalized with heart failure, HFpEF is now as common as heart failure with reduced ejection fraction. We now have many successful treatments for heart failure with reduced ejection fraction, while specific treatment options for HFpEF patients remain elusive. The lack of treatments for HFpEF reflects our very incomplete understanding of this constellation of diseases. There are many pathophysiological factors in HFpEF, but aging appears to play an important role. Here, we propose that aging of the myocardium is itself a specific pathophysiological process. New insights into the aging heart, including hormonal controls and specific molecular pathways, such as microRNAs, are pointing to myocardial aging as a potentially reversible process. While the overall process of aging remains mysterious, understanding the molecular pathways of myocardial aging has never been more important. Unraveling these pathways could lead to new therapies for the enormous and growing problem of HFpEF.

Circulating Growth Differentiation Factor 11/8 Levels Decline With Age

RATIONALE Growth differentiation factor 11 (GDF11) and GDF8 are members of the transforming growth factor-β superfamily sharing 89% protein sequence homology. We have previously shown that circulating GDF11 levels decrease with age in mice. However, a recent study by Egerman et al reported that GDF11/8 levels increase with age in mouse serum. OBJECTIVE Here, we clarify the direction of change of circulating GDF11/8 levels with age and investigate the effects of GDF11 administration on the murine heart. METHODS AND RESULTS We validated our previous finding that circulating levels of GDF11/8 decline with age in mice, rats, horses, and sheep. Furthermore, we showed by Western analysis that the apparent age-dependent increase in GDF11 levels, as reported by Egerman et al, is attributable to cross-reactivity of the anti-GDF11 antibody with immunoglobulin, which is known to increase with age. GDF11 administration in mice rapidly activated SMAD2 and SMAD3 signaling in myocardium in vivo and decreased cardiac mass in both young (2-month-old) and old (22-month-old) mice in a dose-dependent manner after only 9 days. CONCLUSIONS Our study confirms an age-dependent decline in serum GDF11/8 levels in multiple mammalian species and that exogenous GDF11 rapidly activates SMAD signaling and reduces cardiomyocyte size. Unraveling the molecular basis for the age-dependent decline in GDF11/8 could yield insight into age-dependent cardiac pathologies.

Therapeutic Vasculogenesis It Takes Two

See related article, pages 194–202 The shortage of organs for transplantation has been so severe and prolonged that many of us have become almost numb to the crisis facing patients and their families. In 2008, there are 98 992 patients on various organ transplantation waiting lists in the United States alone; during January and February, 4471 transplants were performed but 1044 patients died while on waiting lists.1 This organ crisis shines an unwanted spotlight on the failure of tissue engineering to thus far deliver on its promises of the late 20th century. Tissue engineering in the 21st century still has the same potential, in some ways rediscovering itself under the more reputable moniker of “Regenerative Medicine.” However, some of the problems that kept tissue engineering from delivering the goods in the 1990s remain important ones in this century. One of the critical challenges in building any new organ is the dependence of an implanted tissue construct on sufficient oxygen and nutrient transport for its cells to survive, both for access to substrate molecules and clearance of products of metabolism.2 The principal mechanism for this transport, especially for small molecules, is passive diffusion along concentration gradients, and oxygen diffusion is of obvious importance. The transport of other nutrients is generally more favorable than that of oxygen because the diffusion of oxygen is relatively slow, consumption is high, and the tolerated time for any deficit is so short. To provide sufficient oxygen tension to mitochondria inside the cell, the minimum distance from the cell to the closest capillary lumen in many metabolically active tissues is rarely greater than 40 to 200 μm.3 With this proximity to flowing blood and its partial pressures of ≈100 mm Hg, oxygen can maintain the concentration gradient required at the cell. The distance-to-oxygen …

Targeted Delivery to Cartilage Is Critical for In Vivo Efficacy of Insulin‐like Growth Factor 1 in a Rat Model of Osteoarthritis

Acute articular injuries lead to an increased risk of progressive joint damage and osteoarthritis (OA), and no therapies are currently available to repair or protect the injured joint tissue. Intraarticular delivery of therapeutic proteins has been limited by their rapid clearance from the joint space and lack of retention within cartilage. The aim of this study was to test whether targeted delivery to cartilage by fusion with a heparin‐binding domain would be sufficient to prolong the in vivo function of the insulin‐like growth factor 1 (IGF‐1).

Keep PNUTS in Your Heart

Aging is a major factor in many cardiovascular diseases. The molecular factors that regulate age-related changes in cardiac physiology and contribute to the increased cardiovascular risk in the elderly are not fully understood. A study recently published in Nature suggests a specific role for microRNAs (miRNAs) in regulating cardiac aging and function, challenging the concept that aging is an inevitable process in the heart.