Nutraceutical intervention reverses the negative effects of blood from aged rats on stem cells

Abstract

Aging is associated with a decline in function in many of the stem cell niches of the body. An emerging body of literature suggests that one of the reasons for this decline in function is due to cell non-autonomous influences on the niche from the body. For example, studies using the technique of parabiosis have demonstrated a negative influence of blood from aged mice on muscle satellite cells and neurogenesis in young mice. We examined if we could reverse this effect of aged serum on stem cell proliferation by treating aged rats with NT-020, a dietary supplement containing blueberry, green tea, vitamin D3, and carnosine that has been shown to increase neurogenesis in aged rats. Young and aged rats were administered either control NIH-31 diet or one supplemented with NT-020 for 28 days, and serum was collected upon euthanasia. The serum was used in cultures of both rat hippocampal neural progenitor cells (NPCs) and rat bone marrow-derived mesenchymal stem cells (MSCs). Serum from aged rats significantly reduced cell proliferation as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and 5-bromo-2'-deoxyuridine (BrdU) assays in both NPCs and MSCs. Serum from aged rats treated with NT-020 was not different from serum from young rats. Therefore, NT-020 rescued the effect of serum from aged rats to reduce stem cell proliferation.

Aging leads to altered microglial function that reduces brain resiliency increasing vulnerability to neurodegenerative diseases

“…There is a significant negative effect of old rat serum on the number of dividing stem cells, however, this is reversed with the serum from old rats fed NT-020 (One-way ANOVA F (2,17)=13.64, followed by Sidak’s multiple comparison test *** p <0.001 and * p <0.05). -These trends were also replicated in similar experiments using mesenchymal stem cells (MSC’s) (Bickford et al, 2015). …”

“…In a recent paper we used an in vitro approach designed to mimic parabiosis, where we examined the effect of serum from young and aged rats on proliferation of MSC and NPC’s in culture (Bickford et al, 2015). Furthermore, this study also assessed additional experimental groups that had been treated with a polyphenol rich diet.…”

“…NT-020 is a proof of concept that polyphenolic rich mixtures are capable of modulating several age relevant targets simultaneously, and improve the aging “environment” as well as improve cognition with minimal risk of side effects. We have discussed two recent papers from our group that have shown that NT-020 a polyphenol rich supplement, can reduce the effect of the systemic milieu on stem cell proliferation (Bickford et al, 2015) and to modulate transcription factors involved in response to stress response pathways (Nrf2) (Flowers et al, 2015) and stem cell proliferation as WNT gene expression pathways were also upregulated by NT-020 in that study. Restoring redox balance with polyphenolic rich supplements represents one strategy to reduce microglial priming and thus enhance neural plasticity in the aged brain.…”

Effects of nutraceutical intervention on serum proteins in aged rats

“…As the population ages, there is increased susceptibility to the onset of disease and age-related degenerative conditions, making aging a central area of interest in medical sciences research (Wagster et al 2012;Flowers et al 2016). Aging is a complex and multifactorial physiological process associated with decreased stem cell proliferation in stem cell niches throughout the body, leading to reduced tissue rejuvenation and loss of organ function (Murshid et al 2013;Bickford et al 2015). The decline in stem cell regeneration is global, occurring both in the periphery (Ning et al 2019;Jung et al 2019;Chambers et al 2007) and in the central nervous system (CNS) (Villeda et al 2011;Lazarov et al 2010;Kozareva et al 2019;Ayaz et al 2019;Kase et al 2019;Stankiewicz et al 2019;Bickford et al 2015;Flowers et al 2015;Acosta et al 2010).…”

Human rGDF-11 Counteracts Age-Related Short-Term Memory Impairments in Middle-Aged Mice

“…One possible candidate is Brain Derived Neurotrophic Factor (BDNF), which is known to be involved in neurogenesis, hippocampal learning, and has been suggested to have a co-regulatory relationship with GDF-11 and the TGF-β superfamily (Hall et al, 2000, Lu et al, 2005, Bickford et al, 2015. Another possible contributor is Nerve Growth Factor (NGF), the "archetypical neurotrophin" (Lo, 1995) that is known to have functions directly regulated by GDF-11, such as neuro-differentiation (Ge et al, 2005).…”