Intermittent Heterochronic Plasma Exchange as a Modality for Delaying Cellular Senescence—A Hypothesis

The population of baby boomers (age 60–65) is rapidly increasing globally. The aging of the human body is asso- ciated with the decline of cellular function which leads to the development of a variety of diseases. The increased demand for health care for the aging population creates significant financial burden to any healthcare system. Developing strategies and health intervention methods to ameliorate this situation is paramount. Experiments uti- lizing heterochronic parabiosis in mice have demonstrated that replacing the aging cellular milieu with the plasma of a young experimental animal leads to reversal of cellular senescence. This article describes a hypothetical model of intermittent heterochronic plasma exchange in humans as a modality for heterochronic parabiosis in an attempt to delay cellular senescence. J. Clin. Apheresis 28:387–389, 2013.      VC    2013 Wiley Periodicals, Inc.

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Key words: parabiosis; plasma exchange; cellular senescence

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The demographics of our planet have taken a turn toward rapid growth of older adult population. Predic- tions for 2050 indicate that 2 billion people on earth will be older than 60–65, the age at or near which most countries classify their citizens as seniors. With that population boom looming it is incumbent upon societies to deal with issues and problems of older age, including increasing costs of health care [1].

Recent studies indicate that while baby boomers are living longer, they are not healthier. Aging of the immune system leads to the development of many dis- eases such as infections, autoimmune disorders, and cancer which explains why these ailments are more common in older people. Advances in medicine allow people to live longer despite suffering from chronic disease [1]. Interestingly, the aging of the immune sys- tem and consequently the prevention of these chronic disorders can be ameliorated by systemic perturbations such as nutritional interventions and exercise [2,3].

Advanced age is the main risk factor for most chronic diseases and functional deficit in humans [4]. Cellular senescence contributes to age-related dysfunction by dis- rupting tissue structure and repair and the diminishing ability of the body to constrain the malignant prolifera- tion of tumor cells. Senescent cells accumulate in various tissues and organs and secrete components which cause tissue damage and dysfunction [5].

Recent studies provide evidence that the systemic milieu can inhibit or promote the cellular senescence process in mice.

Heterochronic parabiotic models (shared circulating systems) have demonstrated that exposure of aged pro-

VC   2013 Wiley Periodicals, Inc.

genitor and satellite cells to plasma of young mice restores the proliferation and regenerative capacity of these cells. Conversely, exposing a young mouse to an old systemic environment or plasma lead to impaired cellular and systemic function [5–7] (Fig. 1).

There is a growing body of evidence that telomere dysfunction can contribute to human aging. Telomere dysfunction inhibits the proliferation of B and T lym- phocytes contributing to severe immune dysregulation. Changing the systemic environment of aging telomer- ase knockout (mTere-1-) mice restores normal T lymphopiesis. [8].

These studies strongly suggest that aged plasma con- tains factors which contribute to cellular senescence. Some of these factors have been identified, others remain to be identified. It is also conceivable that young plasma contains factors which contribute to healthy cell proliferation and function.

Therapeutic plasma exchange (TPE) is a well estab- lished therapy for a growing number of medical condi- tions. Its powerful immunomodulatory effect is well documented. TPE has the ability to remove pathogenic

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*Correspondence to: Dobri D. Kiprov, M.D. H.P., Chief, Division of Immunotherapy, California Pacific Medical Center, San Fran- cisco, CA, USA and Medical Director, Apheresis Care Group and Fresenius Medical Care, San Francisco, 1700 California Street, #350, San Francisco, CA 94109, USA. E-mail: dkiprovcai@aol.com

Received 11 June 2013; Accepted 17 June 2013 Published online 27 July 2013 in Wiley Online Library (wileyonlinelibrary.com).

DOI: 10.1002/jca.21286

388 Kiprov

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Fig. 1.   Heterochronic parabiotic models demonstrate that the systemic milieu can inhibit or promote the cellular senescence.

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Fig. 2. Plasma exchange using detergent treated plasma or albumin and intravenous immunoglobulin may be an effective model of human heterochronic parabiosis.

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and proinflammatory factors [9]. In 1982, Kiprov et al. first reported the effect of plasmapheresis on cellular immunity in patients with autoimmune disorders using

monoclonal antibodies and flowcytometry [10]. They demonstrated that plasmapheresis leads to normaliza- tion of the CD4/CD8 ratio of these patients. Numerous studies have confirmed these observations [11–13]. More recent studies have shown that plasmapheresis affects the Th1/Th2 ratio and the production of cyto- kines by these cells [14]. Repeated plasmapheresis leads to the increase of regulatory (CD41CD251 (high) Fox P31) T-cells and clinical improvement in patients with Systemic Lupus Erythematosus [15].

Interesting observations have been made in plasma donors as well. Healthy HIV-positive plasma donors were studied over 2 years. Their CD4 cell count made substantial gains and tended toward stabilizing to nor- mal [16]. In another study, healthy plasma donors showed an increase of serum testosterone levels (Kiprov, Ivanova, personal communication).

The above described animal models of heterochronic parabiosis provide convincing evidence that cellular senescence can be modulated by systemic factors that change with age. Blood borne factors present in the systemic milieu inhibit or promote cell genesis. Plasma exchange is a medical procedure which effectively can remove aging plasma and replace it with fluids that will provide an environment conducive to cell rejuve- nation (Fig. 2). The choice of replacement fluids will be very important. Plasma from young, healthy individ- uals would be an obvious choice. However, obtaining plasma from selected donors, processing and storing it would make the process very cumbersome and cost prohibitive. It is also well documented that the use of fresh frozen plasma as a replacement fluid in plasma exchange procedures is frequently associated with ana- phylactic reactions [17]. Using plasma would also limit the procedure to hospital settings only. In January 2013, the FDA approved detergent treated plasma

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Journal of Clinical Apheresis DOI 10.1002/jca

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(Octaplas) as a pharmaceutical product (www.octaphar- maplasma.com). This will allow its use in an outpatient setting, such as a physician’s office. Cellular immunity changes were observed in patients undergoing TPE with 5% albumin. Therefore, it is conceivable that 5% albumin changes the systemic milieu sufficiently, after removal of inhibiting factors, to allow for cellular regeneration. One may consider the addition of a small amount of intravenous immunoglobulin   (IVIG)   at the end of the plasma exchange procedure. IVIG prepa- rations contain antibodies and cytokines which have been shown to exhibit a positive effect on the immune system and may contribute to establishing an optimal systemic environment for cell growth [18].

Advanced age is the main cause for most chronic disease in humans including many cancers. This leads either to premature death or to physical and/or mental dysfunction which require medical care, including a multitude of medications, many of which have unfavor- able side effects. The cumulative effect is an enormous financial burden to any medical system. If prophylactic plasma exchange can delay cellular immunosenescence it will have a significant beneficial impact on the health of the rapidly increasing aging population and has the potential to markedly decrease the ever expand- ing cost of medical care. A well designed clinical trial is necessary to explore the validity of this hypothesis.

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Journal of Clinical Apheresis DOI 10.1002/jca