1. Department of Neurology and Neurological Sciences and
2. Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA
3. GRECC and Neurology Service, VA Palo Alto Health Care System, Palo Alto, California 94304, USA
4. These authors contributed equally to this work
5. Present addresses: Department of Bioengineering, University of California-Berkeley, Berkeley, California 94720, USA (I.M.C.); Section on Developmental and Stem Cell Biology, Joslin Diabetes Center, Boston, Massachusetts 02215, USA (A.J.W.)

Correspondence to: Thomas A. Rando^1,3 Correspondence and requests for materials should be addressed to T.A.R. (Email: rando@stanford.edu).

Abstract

The decline of tissue regenerative potential is a hallmark of ageing and may be due to age-related changes in tissue-specific stem cells^{1, 2, 3, 4, 5}. A decline in skeletal muscle stem cell (satellite cell) activity due to a loss of Notch signalling results in impaired regeneration of aged muscle^{1, 6}. The decline in hepatic progenitor cell proliferation owing to the formation of a complex involving cEBP- and the chromatin remodelling factor brahma (Brm) inhibits the regenerative capacity of aged liver⁷. To examine the influence of systemic factors on aged progenitor cells from these tissues, we established parabiotic pairings (that is, a shared circulatory system) between young and old mice (heterochronic parabioses), exposing old mice to factors present in young serum. Notably, heterochronic parabiosis restored the activation of Notch signalling as well as the proliferation and regenerative capacity of aged satellite cells. The exposure of satellite cells from old mice to young serum enhanced the expression of the Notch ligand (Delta), increased Notch activation, and enhanced proliferation in vitro. Furthermore, heterochronic parabiosis increased aged hepatocyte proliferation and restored the cEBP- complex to levels seen in young animals. These results suggest that the age-related decline of progenitor cell activity can be modulated by systemic factors that change with age.

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