Aged Stem Cells and Niches Rejuvenated by Systemic Factors; Implications for WILT

Haematopoietic stem cells (HSC) exhibit a range of functional declines during biological aging. There has been comparatively little exploration of the possibility of outside causes for age-related HSC dysfunctions, such as the role of age-related shifts in the systemic and local environment and the aging of the bone marrow niche. In a recent report, Dr. Amy Wagers' group have demonstrated the reality - and the reversibility - of both of these influences on age-related HSC dysfunction.

Haematopoietic stem cells (HSC) and their progeny from exhibit a range of functional declines during biological aging. Most research probing the reasons for these declines have focused on aging damage accumulating in the HSCs themselves, such as the rising burden of oxidative stress and DNA damage (and, as a result, senescent cells) in the compartment. But there has been comparatively little exploration of the possibility of outside causes for age-related HSC dysfunctions, such as the role of age-related shifts in the systemic and local environment and the aging of the bone marrow HSC niche. In a recent report, Dr. Amy Wagers’ stem cell group at Harvard and affiliated institutes1 have demonstrated the reality — and the reversibility — of both of these influences on age-related HSC dysfunction, using an intriguing model of systemic rejuvenation.

The investigators used the heterochronic rodent parabiosis model, in which the circulatory systems of young (2 mo old) and biologically aged (>20 mo) mice are surgically conjoined, allowing their circulatory systems to commingle and equilibrate; as controls, these young-to-old pairs are compared with age-matched pairs of each age group. In an earlier collaboration with Dr. Irina Conboy, Wagers had previously used this captivating experimental system to strikingly demonstrate the rejuvenating effects of exposure to a more youthful systemic environment on skeletal muscle satellite cell mobilization, proliferation, and regenerative capacity, and on the  proliferation of hepatic progenitor cells.7For these new studies in HSC niche function, all parabiotic pairs were composed of partners that differed at the CD45 locus (CD45.1 and CD45.2), allowing haematopoietic cells to be traced to their originating hosts.

Youthful Circulation Restores Youthful Regulation of HSCs in Aged Animals

Comparing isochronic pairs from the 2 age groups, old mice exhibited superfluous accumulations of primitive long-term reconstituting HSCs  relative to young comparitors. These cells were characterized by impaired haematopoietic engraftment, manifested in a less efficient reconstitution of peripheral blood leukocytes, and a bias toward the myeloid lineage at the expense of B-cell development. But all of these changes in old-derived HSC numbers and function were substantially normalized following exposure to the more youthful heterochronic environment (see Figure 1). The frequency and number of bone-forming osteoblasts in aged mice — a constituent of the HSC niche with a central role in regulating HSC number and activity — were also inflated (up to fourfold) in aged mice. Consistent with the findings in the parabiosis model, these old cells induced the development of more HSCs from cocultured  lineage-negative bone marrow cells in vitro than did young-derived bone-forming osteoblasts, possibly explaining the age-related increase in long-term reconstituting HSCs formed in aged animals in vivo.1

Figure 1. Exposure of aged mice to youthful circulatory system restores long-term reconstituting HSC number and function and osteoblastic niche cell number. a: Frequency of endogenous LT-HSCs. b: Frequency of osteoblastic niche cells. c: Reconstitution of haematopoietic system in irradiated recipients by donor bone marrow cells 12 wk posttransplant. From (1).

Rejuvenating Effects of Young Circulation is Mediated by the HSC Niche

The fact that aged animals’ osteoblastic HSC niche cells recapitulate the bias toward excessive accumulation of long-term reconstituting HSC observed in vivo in aged animals suggested that that the effects of a ‘younger’ heterochronic parabiotic systemic environment on old animals’ HSC were the result of an indirect effect, mediated by a rejuvenated HSC niche. Indeed, exposure to a more youthful systemic environment through heterochronic parabiosis normalized the old animals’ frequency and number of bone-forming osteoblasts, and their rate of formation of long-term reconstituting HSCs from lineage-negative bone marrow cells ex vivo.1

More dramatically, lineage-neutral HSCs cocultured with old-derived osteoblastic niche cells demonstrated impaired engraftment and differentiation when transplanted into old or even young irradiated hosts, recapitulating the defects seen in old animals and reinforcing the importance of  the aging of the niche in those defects in the aged host. In contrast, there was no effect of osteoblastic niche cells from aged animals on the engraftment, lineage bias, or reconstituting ability of HSCs from young animals.1

Role of Excess IGF-1 in Impaired HSC Niche Regulatory Function

Exposure of young-derived HSCs to serum derived from aged murine or human donors again led to superfluous long-term reconstituting HSC accumulation, and exposure of aged osteoblastic niche cells to young serum blunted their dysregulatory influence on young-derived cells. Exposure of such cells to aged niche cells also increased their expression of several age-related myeloid-biasing markers, and decreased their expression of lymphoid markers whose expression is known to be reduced in aged organisms, consistent with the observed effects of such cells on lineage in vivo. Notably, these shifts were not observed following coculture with niche cells derived from aged animals that had benefited from the rejuvenating systemic environment of heterochronic parabiosis.1

Further studies to probe the mechanistic basis of the systemic influence on the HSC niche led to the surprising conclusion that a significant mediator of the impaired HSC regulation of the aged osteoblastic HSC niche is an excess of local IGF-1 signaling. Prior exposure of old-derived haematopoietic osteoblastic niche cells or serum to anti-IGF-1antibodies abolished the abnormal accumulation of long-term reconstituting HSCs during coculture with young-derived HSCs. By contrast, anti-IGF-1 Abs had no effect on the influence of young niche on HSCs, nor on old-derived HSCs in isolation. Similar effects were observed on a dose-dependent basis in vivo following neutralizing antibody injection into aged animals’ bone marrows, but not following systemic injection via the peritoneum, showing that the disrupting effect of excessive IGF-1 on HSC function occurs in the haematopoietic niche microenvironment, rather than in the circulation at large, narrowing the effects observed in circulatory parabiosis.1

This counterintuitive finding is superficially opposite to the effects of local IGF-1 expression observed in aging muscle.2 It is instructive, if only by analogy, to compare the contrasting pro- and anti-aging local effects of IGF-1 in aging organisms to the paradoxical findings in other systems, such as the restoration of declining IGF-1 in normally-aging organisms vs. the many models of retarded biological aging in mice and other species characterized by reduced IGF-1 signaling.3 Notably, the effects of these experimental systems on local IGF-1 signaling is in at least some cases tissue-specific: local brain IGF-1 levels and signaling are preserved or enhanced in several models of retarded aging characterized by low systemic IGF-1 levels.4-6 And while systemic IGF-1 levels are low throughout the lifespan in these models, they remain stable at advanced ages when they have declined substantially in normally-aging animals; moreover, Calorie restriction preserves the regulated, pulsatile release of growth hormone with aging (Fig. 2) and selectively retains celllular IGF-1 signaling, even as these capacities are progressively lost in animals fed ad libitum.17-19

Figure 2. Preservation of growth hormone secretory dynamics in by CR in aging Brown Norway rats. From (18)

Implications for Rejuvenation Biotechnology and WILT

Whole-body Interdiction of Lengthening of Telomeres (WILT, or OncoSENS) is proposed by de Grey et al(14,15) as an impregnable defense against cancer, as part of a comprehensive panel of rejuvenation biotechnology to repair the damage and diseases of aging. At its core, it entails the ablation of gene(s) essential to the telomere maintenance machinery (TMM), accompanied by periodic re-seeding of somatic stem-cell pools with autologous cells rendered equally defective for telomere elongation but whose telomeres have been lengthened ex vivo to allow for ongoing tissue repair and maintenance. The strongest challenge to this approach has been the possible existence of functions of TMM other than the lengthening of telomeres itself,8-13 and that even if TMM were dispensible in telomere-elongated stem cells, it might be essential to the functioning of the niche.

SENS Foundation is now funding research by Dr. Zhenyu Ju (formerly a telomerase researcher in Dr. K. Lenhard Rudolph’s laboratory and now at the Max Planck Partner Group on Stem Cell Aging at the Chinese Academy of Medical Sciences) to help resolve the latter question, by monitoring the effects of transplanting telomerase-deficient but ex vivo telomere-extended bone marrow into first normal and then TMM-deficient mice. The finding that the age-related loss of HSC function is substantially attributable to derangement of HSC regulation by the aging niche, much of which is secondary to shifts in systemic factors in the aging niche microenvironment rather than to cell-autonomous defects, provides some very preliminary reassurance on this issue.

More confidently, this latest example of the rejuvenating effect of youthful systemic environment (cf. (7), and Conboy’s later reports in rejuvenation of muscle satellite cell function, as well as loosely-related studies in rejuvenation of the aging female reproductive system) reinforces the expectation that the effects of regenerative engineering therapies will not be narrowly confined to restoring the function of their specific target tissues. As we remove, repair, replace, or render harmless the cellular and molecular damage of aging, the progressive restoration of normal cell and tissue function can be expected to result in a concomitant, progressive normalization of the systemic milieu, as oxidative stress, inflammation, endocrine and paracrine signaling, and other systemic responses to — and sequelae of– the damage of aging are obviated and the body’s inherent maintenance capacities are engaged. With this normalization, these studies suggest, the deranging effects of an aged systemic environment will gradually be alleviated, and remote tissues will begin to return to more youthful function; in turn, the renewal of those remote tissues’ function then further contribute to the re-establishment of youthful homeostasis  in the system as a whole. As the regenerative process feeds back upon itself,  accelerated with each new therapy applied and each additional form of damage repaired, the function of tissues, organs, we may hypothesize that the organism as a whole will re-emerge in unexpected ways and with unanticipated inflection points, until we stand restored to the full health, vigor, and capacity of youth.


1. Mayack SR, Shadrach JL, Kim FS, Wagers AJ. Systemic signals regulate ageing and rejuvenation of blood stem cell niches. Nature. 2010 Jan 28;463(7280):495-500. PubMed PMID: 20110993.

2. Musarò A, McCullagh K, Paul A, Houghton L, Dobrowolny G, Molinaro M, Barton ER, Sweeney HL, Rosenthal N. Localized Igf-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle. Nat Genet. 2001 Feb;27(2):195-200. PubMed PMID: 11175789.

3. Bartke A. Growth hormone and aging: a challenging controversy. Clin Interv Aging. 2008;3(4):659-65. Review. PubMed PMID: 19281058; PubMed Central PMCID: PMC2682398.

4. Adams MM, Elizabeth Forbes M, Constance Linville M, Riddle DR, Sonntag WE, Brunso-Bechtold JK. Stability of local brain levels of insulin-like growth factor-I in two well-characterized models of decreased plasma IGF-I. Growth Factors. 2009 Jun;27(3):181-8. PubMed PMID: 19343576.

5. Sun LY, Evans MS, Hsieh J, Panici J, Bartke A. Increased neurogenesis in dentate gyrus of long-lived Ames dwarf mice. Endocrinology. 2005 Mar;146(3):1138-44. Epub 2004 Nov 24. PubMed PMID: 15564324.

6. Sonntag WE, Lynch CD, Cefalu WT, Ingram RL, Bennett SA, Thornton PL, Khan AS. Pleiotropic effects of growth hormone and insulin-like growth factor (IGF)-1 on biological aging: inferences from moderate caloric-restricted animals. J Gerontol A Biol Sci Med Sci. 1999 Dec;54(12):B521-38. Review. PMID: 10647962

7. Conboy IM, Conboy MJ, Wagers AJ, Girma ER, Weissman IL, Rando TA. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature. 2005 Feb 17;433(7027):760-4. PMID: 15716955

8. Fauce SR, Jamieson BD, Chin AC, Mitsuyasu RT, Parish ST, Ng HL, Kitchen CM, Yang OO, Harley CB, Effros RB. Telomerase-based pharmacologic enhancement of antiviral function of human CD8+ T lymphocytes. J Immunol. 2008 Nov 15;181(10):7400-6. PubMed PMID: 18981163; PubMed Central PMCID: PMC2682219.

9. Ju Z, Jiang H, Jaworski M, Rathinam C, Gompf A, Klein C, Trumpp A, Rudolph KL. Telomere dysfunction induces environmental alterations limiting hematopoietic stem cell function and engraftment. Nat Med. 2007 Jun;13(6):742-7. Epub 2007 May 7. PubMed PMID: 17486088.

10. Passos JF, Saretzki G, von Zglinicki T. DNA damage in telomeres and mitochondria during cellular senescence: is there a connection? Nucleic Acids Res. 2007;35(22):7505-13. PMID: 17986462

11. . Sarin KY, Cheung P, Gilison D, Lee E, Tennen RI, Wang E, Artandi MK, Oro AE, Artandi SE. Conditional telomerase induction causes proliferation of hair follicle stem cells. Nature. 2005 Aug 18;436(7053):1048-52. PMID: 16107853 [PubMed – indexed for MEDLINE]

12. Flores I, Cayuela ML, Blasco MA. Effects of telomerase and telomere length on epidermal stem cell behavior. Science. 2005 Aug 19;309(5738):1253-6. Epub 2005 Jul 21. PMID: 16037417 [PubMed – indexed for MEDLINE]

13. Liu L, DiGirolamo CM, Navarro PA, Blasco MA, Keefe DL. Telomerase deficiency impairs differentiation of mesenchymal stem cells. Exp Cell Res. 2004 Mar 10;294(1):1-8. PMID: 14980495 [PubMed – indexed for MEDLINE]

14. de Grey ADNJ, Campbell FC, Dokal I, Fairbairn LJ, Graham GJ, Jahoda CAB, Porter ACG. Total deletion of in vivo telomere elongation capacity: an ambitious but possibly ultimate cure for all age-related human cancers Ann N Y Acad Sci. 2004 Jun;1019:147-70. PubMed: 15247008.

15. de Grey ADNJ. Whole-body interdiction of lengthening of telomeres: a proposal for cancer prevention. Front Biosci 2005;10:2420-2429. PubMed: 15970505.

16. de Grey AD. WILT: Necessity, feasibility, affordability. In: Fahy GM, West M, Coles LS, Harris SB (eds) The Future of Aging: Pathways to Human Life Extension. 2010; Springer, 667-684.

17. Xu X, Sonntag WE. Moderate caloric restriction prevents the age-related decline in growth hormone receptor signal transduction. J Gerontol A Biol Sci Med Sci. 1996 Mar;51(2):B167-74. PubMed PMID: 8612101.

18. Sonntag WE, Xu X, Ingram RL, D’Costa A. Moderate caloric restriction alters the subcellular distribution of somatostatin mRNA and increases growth hormone pulse amplitude in aged animals. Neuroendocrinology. 1995 May;61(5):601-8. PubMed PMID: 7617139. 

19. D’Costa AP, Lenham JE, Ingram RL, Sonntag WE. Moderate caloric restriction increases type 1 IGF receptors and protein synthesis in aging rats. Mech Ageing Dev. 1993 Oct 1;71(1-2):59-71. PubMed PMID: 7508538.

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