Life Extension Magazine April 2011
University of California Researchers Restore Immune Function in Aging Human Cells
By Delia Wilder
An analog of a previously banned drug may have yielded a significant age-reversal breakthrough.
Aging of the immune system, known as immunosenescence, plays a central role in the overall degeneration of the human body. (See article Innovative Strategy for Combating Immunosenescence)
Scientists at the University of California San Francisco and the National Institute on Aging1 have successfully reversed age-related deterioration in immune cell function using lenalidomide, a relative of the infamous drug thalidomide.
In older humans, decreased generation of cell signaling molecules like interferon-gamma (IFN-gamma) by white blood cells reduces the ability of the aging immune system to kill intracellular microbes and eliminate cancer cells.2
Lenalidomide provides intriguing immune-boosting properties, including an increase in production of cell signaling molecules that mobilize vital immune system cells like T-helper white blood cells and natural killer cells. In fact, recent scientific data shows that lenalidomide helps to normalize output of critical immune signaling molecules like interferon-gamma and IL-2, known to be reduced in white blood cells taken from individuals 65 and older.1
Even more remarkable, these effects were observed at exceedingly low doses. This study has huge implications. We need normally functioning immune cells to fend off cancer and infection as we mature—precisely the kinds of conditions to which many people succumb as they and their immune systems decline with aging.
In this article, the results of this groundbreaking study are detailed. You will also learn how these findings relate to your immune system’s health and function.
New Benefits from an Old Drug
In the late 1950s and early ‘60s, thousands of children suffered severe birth defects after their mothers took thalidomide, a sedative then used to prevent nausea in pregnancy.3 That catastrophe led to the complete withdrawal of the drug from the market worldwide and stifled research investigation into beneficial immune-boosting properties of the drug over the following thirty years. At the start of the new millennium, however, scientific interest was reawakened as scientists studied thalidomide’s impact on the immune system in certain skin conditions.4
Given the teratogenic effects (i.e., birth defects) caused by thalidomide, new research began to focus upon “second-generation” drugs.5 As a result, lenalidomide has significantly changed the management of diseases such as multiple myeloma, myelodysplastic syndrome, and some leukemias, all of which arise from disruptions of the T- and B-cell command and control system.5-10 The drug is now also finding a role in management of certain challenging solid tumors such as those of the kidney and lung.11-14
Lenalidomide directly kills cancer cells and limits tumor growth.8,15-17 It is the drug’s immunomodulatory potential, however, that attracted the attention of the UCSF researchers.1
Lenalidomide specifically stimulates T-helper and natural killer cells, in large part by promoting production of cytokine IL-2.6 Research clearly indicates that aging is associated with reduced levels of both IL-2 and the IL-2 receptor on cell surfaces. For example, comparison of white blood cells from younger donors (less than 40 years of age) with older donors (greater than 60 years of age) shows reduced levels of both IL-2 and the IL-2 receptor.18
IL-2 helps T-helper and natural killer cells against invading infectious agents such as bacteria and viruses. Lenalidomide also inhibits T-suppressor cells that prematurely shut down immune function, thus allowing cytotoxic and natural killer cells to exert their beneficial effects against cancer cells.14 Lenalidomide has potent immunomodulatory effects upon inflammation.16,19 For example, lenalidomide inhibits production of pro-inflammatory cytokines like TNF-alpha, IL-1, IL-6, and IL-12 and elevates the production of the anti-inflammatory cytokine IL-10 from human white blood cells.20
What does all this have to do with aging? Plenty, when we remember that immunosenescence involves decreases in the very T-cell numbers and functions that lenalidomide enhances. That’s what led Dr. Edward J. Goetzl and his team at UCSF to explore lenalidomide for the first time as an anti-immunosenescence drug.
The UCSF Study of Lenalidomide and Aging
Dr. Goetzl is a world-renowned expert in human aging and an immunologist. When Dr. Goetzl and his team explored the benefits of lenalidomide on cancer, it led to their breakthrough work demonstrating lenalidomide’s astonishing effects on immunosenescent cells.1
The team obtained T-cells from a group of healthy young adults aged 21-40 years, and also from adults 65 years and older. They stimulated the T-cells to mimic an infection or invader, using standard laboratory techniques. Next, they incubated the stimulated cells with lenalidomide, keeping some stimulated T-cells untreated as controls. Finally, they measured a host of T-cell functions along with other factors.1
The results from their study may change the direction of treatment for the aging immune system.
Lenalidomide-treated T-cells from young subjects increased their IL-2 production 17-fold, and that of IFN-gamma 3-fold, a remarkable increase. However, the same concentrations of lenalidomide, used to treat T-cells from the older subjects, produced an astonishing 120-fold increase in IL-2, and a 6-fold increase in IFN-gamma. What these results mean is that lenalidomide restores and sustains levels of the very cells and cytokines that otherwise diminish with aging.
That’s not all. Lenalidomide increased production of helper T-cells from older subjects, and suppressed the apoptosis to which older people’s T-cells are especially vulnerable.1 Furthermore, it restored T-cells’ ability to move toward a chemical stimulus to levels indistinguishable from that of younger subjects’ cells.1 Finally, lenalidomide treatment reduced production of the pro-inflammatory cytokine TNF-alpha from other immune cells called macrophages.
Cancer treatment regimens use doses as high as 50 mg/day for several weeks at a time.7 But the dosing of lenalidomide used in the UCSF study were estimated to be equivalent to those attainable by oral doses of just 1-3 mg, and they produced their beneficial effects for up to 5 days after a single treatment.1
Acknowledging the astounding results of lenalidomide treatment at such tiny doses, Dr. Goetzl recently said, “If you could take a low-dosage pill with no side effects, wouldn’t you do it?”21
The team has big plans for next steps. Concluding the report of this first study, they write, “Future testing of low-dose lenalidomide will focus on its potential roles in improving diverse aspects of immunity in the elderly population, ranging from the effectiveness of vaccines to host defenses against microbial infections to resistance to cancers.”1
So how might low-dose lenalidomide help the aging immune system?
The answer is it may help restore cell signaling of the aging immune system to the level of a healthy young adult. For example, young people get cancer at a small fraction of the rates of older adults. One reason is the steady patrolling of the young person’s body by a healthy, vigorous immune system. The youthful immune system “looks for” aberrant, potentially cancerous cells and destroys them before they can proliferate out of control. As another example, infection from influenza (“the flu”) and bacterial pneumonia can be quite dangerous in the elderly, while younger individuals suffer from far less mortality from these types of infectious diseases. An important reason for this difference is the vigorous response of the youthful immune system toward invading microbes in contrast to the sluggish response of the aging immune system.
However, more work needs to be done to better understand lenalidomide’s effects upon the immune system before widespread use for immunosenescence treatment in aging humans.
For example, low-dose lenalidomide seemed to have different effects upon IL-17 in younger vs. older human test subjects’ white blood cells.1 The implications are that low-dose lenalidomide in older subjects would not be expected to impair recruitment of neutrophils (a type of white blood cell), nor increase the risk of immune system attacking healthy tissues (autoimmunity) through excessive mobilization and activation of T-helper cells and related subsets of T-effector cells. Clearly, more work needs to be done to understand the benefits and limitations of low-dose lenalidomide on the aging immune system in humans.
The concept of immunosenescence explains why the aging immune system gradually weakens and leaves us vulnerable. Lenalidomide in low doses appears to hold promise for restoring the aging immune system to more youthful, vibrant function.
The progressive deterioration of the immune system with age, known as immunosenescence, has long been assumed to be inevitable. It underlies the cause of death in the majority of older adults, especially the very old, who succumb to infections and cancers that a vigorous, healthy immune system can resist. Thanks to the work of Dr. Edward J. Goetzl and his devoted team of scientists, however, immunosenescence may soon take its place among the growing list of treatable consequences of aging. Their work with lenalidomide demonstrates the potential power of immunomodulation using tiny doses of a drug. Their recent study suggests that lenalidomide can boost age-related impairments in the all-important T-helper and natural killer cell populations, while tamping down the activity of T-regulatory cells that would otherwise suppress immune function. Astonishingly, low-dose lenalidomide can restore some T-cell functions to levels identical with those of healthy young adults. Although more work needs to be done to fully understand the benefits and risks associated with low-dose lenalidomide, Dr. Goetzl’s work holds great promise to usher in a new age of discovery and research sure to benefit older people with evidence of immunosenescence.
If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.
1. Huang MC, Greig NH, Luo W, et al. Preferential enhancement of older human T cell cytokine generation, chemotaxis, proliferation and survival by lenalidomide. Clin Immunol. 2010 Dec 1.
2. Available at: http://aaas.confex.com/aaas/2010/webprogram/Paper1085.html. Accessed February 7, 2011.
3. Palgan K, Palgan I. Thalidomide—new prospective therapy in oncology. Wiad Lek. 2003;56(9-10):455-9.
4. Moraes M, Russo G. Thalidomide and its dermatologic uses. Am J Med Sci. 2001 May;321(5):321-6.
5. Knight R. IMiDs: a novel class of immunomodulators. Semin Oncol. 2005 Aug;32(4 Suppl 5):S24-30.
6. Anderson KC. Lenalidomide and thalidomide: mechanisms of action—similarities and differences. Semin Hematol. 2005 Oct;42(4 Suppl 4):S3-8.
7. Blum W, Klisovic RB, Becker H, et al. Dose escalation of lenalidomide in relapsed or refractory acute leukemias. J Clin Oncol. 2010 Nov 20;28(33):4919-25.
8. Dimopoulos MA, Terpos E. Lenalidomide: an update on evidence from clinical trials. Blood Rev. 2010 Nov;24 Suppl 1:S21-6.
9. Li S, Gill N, Lentzsch S. Recent advances of IMiDs in cancer therapy. Curr Opin Oncol. 2010 Nov;22(6):579-85.
10. Morgan G. Future drug developments in multiple myeloma: an overview of novel lenalidomide-based combination therapies. Blood Rev. 2010 Nov;24 Suppl 1:S27-32.
11. Amato RJ, Hernandez-McClain J, Saxena S, Khan M. Lenalidomide therapy for metastatic renal cell carcinoma. Am J Clin Oncol. 2008 Jun;31(3):244-9.
12. Patel PH, Kondagunta GV, Schwartz L, et al. Phase II trial of lenalidomide in patients with metastatic renal cell carcinoma. Invest New Drugs. 2008 Jun;26(3):273-6.
13. Corti A, Giovannini M, Belli C, Villa E. Immunomodulatory agents with antivascular activity in the treatment of non-small cell lung cancer: focus on TLR9 agonists, IMiDs and NGR-TNF. J Oncol. 2010;2010:732680.
14. Dalgleish A, Galustian C. The potential of immunomodulatory drugs in the treatment of solid tumors. Future Oncol. 2010 Sep;6(9):1479-84.
15. Davies F, Baz R. Lenalidomide mode of action: linking bench and clinical findings. Blood Rev. 2010 Nov;24 Suppl 1:S13-9.
16. Heise C, Carter T, Schafer P, Chopra R. Pleiotropic mechanisms of action of lenalidomide efficacy in del(5q) myelodysplastic syndromes. Expert Rev Anticancer Ther. 2010 Oct;10(10):1663-72.
17. Saloura V, Grivas PD. Lenalidomide: a synthetic compound with an evolving role in cancer management. Hematology. 2010 Oct;15(5):318-31.
18. Nagel JE, Chopra RK, Chrest FJ, et al. Decreased proliferation, interleukin 2 synthesis, and interleukin 2 receptor expression are accompanied by decreased mRNA expression in phytohemagglutinin-stimulated cells from elderly donors. J Clin Invest. 1988 Apr;81(4):1096-102.
19. Ladizinski B, Shannon EJ, Sanchez MR, Levis WR. Thalidomide and analogues: potential for immunomodulation of inflammatory and neoplastic dermatologic disorders. J Drugs Dermatol. 2010 Jul;9(7):814-26.
20. Kotla V, Goel S, Nischal S, et al. Mechanism of action of lenalidomide in hematological malignancies. J Hematol Oncol. 2009 Aug 12;2:36.
21. Available at: http://www.sciencedaily.com/releases/2010/12/101213140945.htm. Accessed January 19, 2011.
22. Effros RB. Ageing and the immune system. Novartis Found Symp. 2001;235:130-9; discussion 139-45, 146-9.
23. Caruso C, Buffa S, Candore G, et al. Mechanisms of immunosenescence. Immun Ageing. 2009 Jul 22;6:10.
24. Rea IM, Stewart M, Campbell P, Alexander HD, Crockard AD, Morris TC. Changes in lymphocyte subsets, interleukin 2, and soluble interleukin 2 receptor in old and very old age. Gerontology. 1996;42(2):69-78.
25. Pawelec G, Derhovanessian E, Larbi A. Immunosenescence and cancer. Crit Rev Oncol Hematol. 2010 Aug;75(2):165-72.
26. Johnson SA, Cambier JC. Ageing, autoimmunity and arthritis: senescence of the B cell compartment - implications for humoral immunity. Arthritis Res Ther. 2004;6(4):131-9.
27. Agius E, Lacy KE, Vukmanovic-Stejic M, et al. Decreased TNF-alpha synthesis by macrophages restricts cutaneous immunosurveillance by memory CD4+ T cells during aging. J Exp Med. 2009 Aug 31;206(9):1929-40.
28. Dorshkind K, Montecino-Rodriguez E, Signer RA. The ageing immune system: is it ever too old to become young again? Nat Rev Immunol. 2009 Jan;9(1):57-62.
29. Marko MG, Ahmed T, Bunnell SC, et al. Age-associated decline in effective immune synapse formation of CD4(+) T cells is reversed by vitamin E supplementation. J Immunol. 2007 Feb 1;178(3):1443-9.
30. Caruso C, Candore G, Cigna D, et al. Cytokine production pathway in the elderly. Immunol Res. 1996;15(1):84-90.
31. Swain S, Clise-Dwyer K, Haynes L. Homeostasis and the age-associated defect of CD4 T cells. Semin Immunol. 2005 Oct;17(5):370-7.
32. Gillis S, Kozak R, Durante M, Weksler ME. Immunological studies of aging. Decreased production of and response to T cell growth factor by lymphocytes from aged humans. J Clin Invest. 1981 Apr;67(4):937-42.
33. Kilpatrick RD, Rickabaugh T, Hultin LE, et al. Homeostasis of the naive CD4+ T cell compartment during aging. J Immunol. 2008 Feb 1;180(3):1499-507.
34. Fagnoni FF, Vescovini R, Passeri G, et al. Shortage of circulating naive CD8(+) T cells provides new insights on immunodeficiency in aging. Blood. 2000 May 1;95(9):2860-8.
35. Wack A, Cossarizza A, Heltai S, et al. Age-related modifications of the human alphabeta T cell repertoire due to different clonal expansions in the CD4+ and CD8+ subsets. Int Immunol. 1998 Sep;10(9):1281-8.
36. Gregg R, Smith CM, Clark FJ, et al. The number of human peripheral blood CD4+ CD25high regulatory T cells increases with age. Clin Exp Immunol. 2005 Jun;140(3):540-6.
37. Lages CS, Suffia I, Velilla PA, et al. Functional regulatory T cells accumulate in aged hosts and promote chronic infectious disease reactivation. J Immunol. 2008 Aug 1;181(3):1835-48.