Correspondence

Hutchinson–Gilford Progeria Syndrome

N Engl J Med 2008; 358:2409-2411May 29, 2008

Article

To the Editor:

In an otherwise elegant clinical description of the Hutchinson–Gilford progeria syndrome by Merideth and colleagues (Feb. 7 issue),1 we take exception to the authors' suggestion that their findings have overarching significance with respect to an understanding of normal aging. Although some of the changes that characterize the Hutchinson–Gilford progeria syndrome look like aging, other characteristic features of the syndrome (e.g., elevated platelet counts, prolonged prothrombin times, and functional oral deficits) do not. Moreover, certain prominent features of human aging — for example, the activation of inflammatory pathways — are not typical of the Hutchinson–Gilford progeria syndrome.

On the basis of studies in mice, it is likely that every organ undergoes distinct molecular changes with age.2-4 Authentic genetic models of accelerated aging should not only give rise to phenotypes that mimic aging but also produce changes in gene expression that are typical of normal aging. This is not the case for the Hutchinson–Gilford progeria syndrome or other progeria syndromes. It is time to relinquish the myth that the Hutchinson–Gilford progeria syndrome and related “progeria” syndromes hold the key to an understanding of aging. This is a convenient and hopeful conclusion, but it is inconsistent with what is known about aging.

William B. Ershler, M.D.
Luigi Ferrucci, M.D., Ph.D.
Dan L. Longo, M.D.
National Institute on Aging, Baltimore, MD 21225

4 References

1. 1

   Merideth MA, Gordon LB, Clauss S, et al. Phenotype and course of Hutchinson-Gilford progeria syndrome. N Engl J Med 2008;358:592-604
   Full Text | Web of Science | Medline

2. 2

   Lustig A, Weeraratna AT, Wood WW III, et al. Transcriptome analysis of age-, gender-, and diet-associated changes in murine thymus. Cell Immunol 2007;245:42-61
   CrossRef | Web of Science | Medline

3. 3

   Xu X, Zhan M, Duan W, et al. Gene expression atlas of the mouse central nervous system: impact and interactions of age, energy intake and gender. Genome Biol 2007;8:R234-R234
   CrossRef | Web of Science | Medline

4. 4

   Zahn JM, Poosala S, Owen AB, et al. AGEMAP: a gene expression database for aging in mice. PLoS Genet 2007;3:e201-e201
   CrossRef | Web of Science | Medline

To the Editor:

The lamin A gene (LMNA) mutation in the Hutchinson–Gilford progeria syndrome results in the synthesis of progerin. How progerin causes the clinical phenotype is poorly understood. Dysregulated gene expression is one possibility. The search for dysregulated genes may be based on the phenotypic characterization. Merideth et al. report a previously unrecognized phenotypic feature of progeria — namely, elevated serum phosphorus levels associated with an inappropriately low fractional excretion of phosphorus and normal creatinine clearance. Hyperphosphatemia and evidence of accelerated aging are features of klotho deficiency and fibroblast growth factor (FGF)–23 deficiency in mice.1-3 Klotho is a hormone secreted by the kidney that has several roles, including its role as a cofactor that is essential for activation of FGF-receptor signaling by FGF-23.2 FGF-23 is a phosphaturic hormone that increases the fractional excretion of phosphate.3 Correction of hyperphosphatemia in Fgf-23 ^−/− mice or klotho ^−/− mice by targeting vitamin D reduces the accelerated aging that is characteristic of the model.3,4 The hypothesis that disruption of the klotho–FGF-23 axis is one potentially treatable downstream consequence of the expression of progerin should be explored.

Alberto Ortiz, M.D.
Fundacion Jimenez Diaz, 28040 Madrid, Spain
aortiz@fjd.es

4 References

1. 1

   Kuro-o M, Matsumura Y, Aizawa H, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 1997;390:45-51
   CrossRef | Web of Science | Medline

2. 2

   Urakawa I, Yamazaki Y, Shimada T, et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 2006;444:770-774
   CrossRef | Web of Science | Medline

3. 3

   Razzaque MS, Sitara D, Taguchi T, St-Arnaud R, Lanske B. Premature aging-like phenotype in fibroblast growth factor 23 null mice is a vitamin D-mediated process. FASEB J 2006;20:720-722
   Web of Science | Medline

4. 4

   Tsujikawa H, Kurotaki Y, Fujimori T, Fukuda K, Nabeshima Y. Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system. Mol Endocrinol 2003;17:2393-2403
   CrossRef | Web of Science | Medline

Author/Editor Response

We agree with Ershler et al. that the Hutchinson–Gilford progeria syndrome does not perfectly model the aging process, just as, for instance, familial hypercholesterolemia does not produce every characteristic of coronary artery disease and alpha₁-antitrypsin deficiency does not exactly recapitulate emphysema. In these examples, however, important insights may be derived from imperfect models, and certain aspects of the aging process may be informed by the Hutchinson–Gilford progeria syndrome. In fact, evidence continues to accrue in support of a role of progerin, the abnormal lamin A protein that accumulates in the Hutchinson–Gilford progeria syndrome, in promoting aging. Specifically, increasing levels of progerin are found in normal cells as people age,1 and individual cells with increased progerin show nuclear membrane abnormalities.2 Furthermore, levels of progerin accumulate with age in the skin of normal persons.3

Regarding the relationship between hyperphosphatemia and aging, our data indicate that the set point for renal phosphorus (phosphate) reabsorption in the Hutchinson–Gilford progeria syndrome may be slightly altered; the fractional excretion of phosphate, although within normal limits, may be relatively low, allowing serum phosphorus to remain high. Ortiz suggests that impaired renal expression of klotho and Fgf-23 may account for this. Our own data, as well as published information,4,5 indicate that the expression of KLOTHO and FGF-23 is not affected by the Hutchinson–Gilford progeria syndrome, at least not in skin fibroblasts.

Melissa A. Merideth, M.D., M.P.H.
Francis S. Collins, M.D., Ph.D.
William A. Gahl, M.D., Ph.D.
National Human Genome Research Institute, Bethesda, MD 20892
bgahl@helix.nih.gov

5 References

1. 1

   Scaffidi P, Misteli T. Lamin A-dependent nuclear defects in human aging. Science 2006;312:1059-1063
   CrossRef | Web of Science | Medline

2. 2

   Cao K, Capell B, Erdos MR, Djabali K, Collins FSA. A lamin A protein isoform overexpressed in Hutchinson-Gilford progeria syndrome interferes with mitosis in progeria and normal cells. Proc Natl Acad Sci U S A 2007;104:4949-4954
   CrossRef | Web of Science | Medline

3. 3

   McClintock D, Ratner D, Lokuge M, et al. The mutant form of lamin A that causes Hutchinson-Gilford progeria is a biomarker of cellular aging in human skin. PLoS ONE 2007;2:e1269-e1269
   CrossRef | Web of Science | Medline

4. 4

   Csoka AB, English SB, Simkevich CP, et al. Genome-scale expression profiling of Hutchinson-Gilford progeria syndrome reveals widespread transcriptional misregulation leading to mesodermal/mesenchymal defects and accelerated atherosclerosis. Aging Cell 2004;3:235-243
   CrossRef | Web of Science | Medline

5. 5

   Ly DH, Lockhart DJ, Lerner RA, Schultz PG. Mitotic misregulation and human aging. Science 2000;287:2486-2492
   CrossRef | Web of Science | Medline

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