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Health Protocols

Immune Senescence

Novel And Emerging Interventions

Parabiosis and Immune Function

Research dating back to the late 1800s is the basis of burgeoning interest in the anti-aging effects of so-called young blood. The experimental procedure that initially proved that animals’ circulatory systems could grow together and become joined (Bert 1864), referred to as parabiosis, was later used to demonstrate that older mice can live longer when their circulation is joined to younger mice (Ludwig 1972).

In early animal research, pairing old and young mice through parabiosis was found to have a positive impact on the bone density of the old mice (Horrington 1960). More recent animal research suggests parabiosis can help restore youthful tissue-regenerating activity in older stem cells (Conboy 2005). In one compelling study, growth and development of neurons were found to increase in old mice, and decrease in young mice, when their circulatory systems were connected (Mendelsohn 2011). Another study found brain plasticity and cognitive function were notably enhanced in aged mice joined through parabiosis to young mice. The authors of this study commented, “exposure of an aged animal to young blood can counteract and reverse pre-existing effects of brain aging at the molecular, structural, functional and cognitive level” (Villeda 2014).

The effects of young blood on older animals are believed to be mediated, at least in part, by immunologic mechanisms. Emerging evidence suggests age-related diminishment of regenerative capacity in tissues such as muscles and neurons may be related to changes in immune signaling (Schiaffino 2016; Villeda 2013). Parabiosis has also been demonstrated to transfer immune tolerance: animal experiments have demonstrated that parabiosis can dampen or eliminate toxic immune reactions to foreign chemicals and tissue transplants (Polak 1975; Andresen 1957). This ability to transfer immune tolerance from one organism to another may have implications for future research into treatments for conditions related to immune hyperactivity, such as autoimmune diseases and allergies.

Researchers are exploring the possibility that one or more components of young blood might be able to reverse some aspects of immune aging in humans; conversely, there may be factors in old blood that disrupt normal stem cell activity and trigger immune system aging (Pishel 2012; Mendelsohn 2011).

One factor in young blood identified as potentially responsible for some anti-aging effects is called growth differentiation factor 11, or GDF11. Some research suggests levels of GDF11 decline with age, and restoration of GDF11 levels may reverse some manifestations of aging (Loffredo 2013). However, this area of research remains controversial, as not all studies have confirmed the anti-aging effects of GDF11 (Hinken 2016).

Recently, an alternative theory explaining the benefits of young blood transfusions has emerged. This newer perspective suggests that rather than providing anti-aging factors to older transfusion recipients, young blood may dilute concentrations of pro-aging factors that accumulate with age in the blood of older individuals. And indeed, old blood transfused into young animals has been shown to exert detrimental pro-aging effects in several tissue types as well as diminish some measures of physical performance (Rebo 2016).

Life Extension and other forward-thinking research organizations are currently organizing clinical studies that will help clarify the potential therapeutic benefits of factors in young blood and/or removal of pro-aging factors in old blood. Those interested in more information about these initiatives can fill out the information request form on this webpage: http://health.lifeextension.com/LandingPages/Stem.aspx

As of late-2016, an ongoing trial is investigating the effects of transfusions of plasma from individuals aged 16 to 25 into those aged 35 or older. This trial will assess the effects of these young-blood transfusions on a battery of biomarkers of aging (Ambrosia LLC 2016). Data from this and other similar trials promise to help establish the theoretical and practical framework that may allow this novel therapy to help aging individuals avoid the perils of immune senescence.

Granulocyte-colony Stimulating Factor

Granulocyte-colony stimulating factor (G-CSF) is a protein growth factor made by the body that stimulates production of neutrophils in the bone marrow. A G-CSF drug, filgrastim (Neupogen), is used to bolster low neutrophil counts and decrease risk of infection, particularly in some patients undergoing chemotherapy. Filgrastim can also increase the migration of blood-forming stem cells from the bone marrow into circulation (Arvedson 2015; Brender 2006; Bendall 2014; Gold Standard 2016).

Age-related immune senescence leads to reduced neutrophil function, mobility, and antibacterial activity (Butcher 2000; McLaughlin 1986; Schröder 2003). In a laboratory study, treatment of aged neutrophils with G-CSF resulted in improvement in their function and mobility, and an increase in the number of viable neutrophils (Wolach 2007).

One pioneering physician in South Florida, Dipnarine Maharaj, MD, has explored utilizing G-CSF to activate lymphoid stem cells and combat immune senescence (Maharaj 2014).

Overall, there is evidence to suggest G-CSF may represent a novel tool in the battle against age-related immune senescence. Continued research in this area is needed to improve our understanding of how neutrophils and overall immune system function in older individuals will respond to G-CSF treatment.

Senolytic Activators

Senolytic activators represent an exciting class of emerging therapeutics in aging science. They selectively target senescent cells (ie, cells that have stopped dividing properly and can promote an inflammatory response) and remove them or decrease their negative impact. Senescent cells have been implicated in many age-related diseases. Senolytic agents may improve cardiovascular functioning, promote bone health, increase insulin sensitivity, support healthy metabolism, and rejuvenate stem cells (Soto-Gamez 2017).

Quercetin plus Dasatinib. Quercetin, a bioflavonoid found in foods such red wine, onions, apples, berries, and green tea, has potent anti-inflammatory and free radical-scavenging properties. It has been shown to induce cell death in senescent cells, decreasing their numbers in human fat tissue cultures (Zhu 2015). The combination of quercetin plus dasatinib, a chemotherapy drug that inhibits cell proliferation, was also found to decrease the secretion of proinflammatory cytokines associated with age-related frailty by senescent cells (Xu 2018). It has also been postulated that quercetin may silence expression of pro-survival gene networks in senescent cells, helping facilitate cell death of dysfunctional, senescent cells (Zhu 2015).

In animal research, intermittent oral administration of quercetin plus dasatinib—to naturally aged mice and young mice that received transplanted senescent cells—improved physical function and increased post-treatment survival by 36% (Xu 2018). In addition, a single course of quercetin plus dasatinib reduced senescent cell burden, improved heart and blood vessel function, and increased exercise capacity in mice. Periodic administration extended the lifespan of some mice, delaying age-related pathology and dysfunction long after treatment was discontinued (Zhu 2015).

Theaflavins. Theaflavins are some of the polyphenolic compounds that add red hues to black tea. Preclinical evidence indicates these compounds may have beneficial effects against cancer, atherosclerosis, obesity, osteoporosis, periodontal disease, inflammatory disorders, and bacterial and viral infections (Noberini 2012; Takemoto 2018). Theaflavins and other black tea polyphenols appear to inhibit tyrosine kinases, a group of enzymes involved in cell proliferation, and may also suppress certain tissue growth factors involved in senescence (Noberini 2012; Tominaga 2015).

In one study, a black tea extract containing theaflavins extended the lives of fruit flies by altering gene expression and reducing oxidative stress (Peng 2009). Another study showed theaflavins decreased radiation-induced senescence and oxidative stress in blood-cell-producing stem cells and prolonged survival in certain groups of irradiated mice (Han 2017).

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