Plasma dilution improves cognition and attenuates neuroinflammation in old mice

Abstract

Our recent study has established that young blood factors are not causal, nor necessary, for the systemic rejuvenation of mammalian tissues. Instead, a procedure referred to as neutral blood exchange (NBE) that resets signaling milieu to a pro-regenerative state through dilution of old plasma, enhanced the health and repair of the muscle and liver, and promoted better hippocampal neurogenesis in 2-year-old mice (Mehdipour et al., Aging 12:8790–8819, 2020). Here we expand the rejuvenative phenotypes of NBE, focusing on the brain. Namely, our results demonstrate that old mice perform much better in novel object and novel texture (whisker discrimination) tests after a single NBE, which is accompanied by reduced neuroinflammation (less-activated CD68+ microglia). Evidence against attenuation/dilution of peripheral senescence-associated secretory phenotype (SASP) as the main mechanism behind NBE was that the senolytic ABT 263 had limited effects on neuroinflammation and did not enhance hippocampal neurogenesis in the old mice. Interestingly, peripherally acting ABT 263 and NBE both diminished SA-βGal signal in the old brain, demonstrating that peripheral senescence propagates to the brain, but NBE was more robustly rejuvenative than ABT 263, suggesting that rejuvenation was not simply by reducing senescence. Explaining the mechanism of the positive effects of NBE on the brain, our comparative proteomics analysis demonstrated that dilution of old blood plasma yields an increase in the determinants of brain maintenance and repair in mice and in people. These findings confirm the paradigm of rejuvenation through dilution of age-elevated systemic factors and extrapolate it to brain health and function.

Heterochronic blood exchange attenuates age-related neuroinflammation and confers cognitive benefits: do microvascular protective effects play a role?

“…On one hand, such effects could be elicited by an anti-geronic factor(s) passing to the older animal to restore youthful function, but the old environment also may unintentionally benefit in this setting from the dilution of potential bad actors, and in the case of parabiosis, the sharing of young organs during this chronic exchange. Indeed, this is what is demonstrated here by Mehdipour et al [5] whereby a single neutral blood exchange (NBE) in old mice improved multiple facets of brain health, including cognitive function, neuroinflammation and markers of senescence [5], which is consistent with prior reports from the Conboy lab [6]. Interestingly, the effect of blood dilution may be even more fascinatingly interesting and complex than previously appreciated, in that the apparent relenting of pro-geronic factors via dilution acted to "reset" a plethora of circulating factors in the old environment, which could in turn mediate at least some of the beneficial effects in this model.…”

“…However, as with most any experimental paradigm, heterochronic parabiosis and exchange consists of caveats and limitations that must be appreciated when interpreting results. One such scenario arises in instances where apparent rejuvenation is observed, as suggested by Mehdipour et al [5] and prior work from the Conboy laboratory [6]. On one hand, such effects could be elicited by an anti-geronic factor(s) passing to the older animal to restore youthful function, but the old environment also may unintentionally benefit in this setting from the dilution of potential bad actors, and in the case of parabiosis, the sharing of young organs during this chronic exchange.…”

Attenuation of age-elevated blood factors by repositioning plasmapheresis: A novel perspective and approach

“…These pro-geronic factors can be removed by plasmapheresis. Interestingly, our recent papers highlight broadly positive effects of old plasma dilution on tissue health and regeneration [9,13]. These studies suggest that simply the removal of pro-geronic factors rapidly and robustly rejuvenated multiple organs in aged mice and improves their cognition.…”

“…In these regards, it is interesting that peripherally acting senolytic ABT263 diminished brain senescence yet failed to robustly improve brain health in old mice [13]. At the same time, neutral blood exchange that also acts peripherally and dilutes old systemic milieu had a profound multi-faceted rejuvenating effects, not only improving neurogenesis and reducing neuro-inflammation, but enhancing cognitive capacity of the old mice [13]. These results suggest that TPE/NBE do not act simply by diluting SASP.…”

“…For example, in transplantation experiments or through senolytic studies, senescent cells were proposed to exacerbate such age-associated diseases, as cancer, osteoarthritis, osteoporosis, atherosclerosis, Parkinson's diseases, and Alzheimer's. In these regards, it is interesting that peripherally acting senolytic ABT263 diminished brain senescence yet failed to robustly improve brain health in old mice [13]. At the same time, neutral blood exchange that also acts peripherally and dilutes old systemic milieu had a profound multi-faceted rejuvenating effects, not only improving neurogenesis and reducing neuro-inflammation, but enhancing cognitive capacity of the old mice [13].…”