Frailty is a geriatric syndrome associated with both locomotor and cognitive decline, implicated in both poor quality of life and negative health outcomes. One central question surrounding frailty is whether phenotypic frailty is associated with the cognitive impairment during aging. Using spontaneous behavioral tests and by studying the dynamic change during aging, we demonstrated that the two form of vulnerability, locomotor and recognition memory decline, develop in parallel and therefore, integration of the motoric and cognitive evaluations are imperative. We developed an integrated frailty index based on both phenotypic and recognition memory performances. Hericium erinaceus (H. erinaceus) is a medicinal mushroom that improves recognition memory in mice. By using HPLC-UV-ESI/MS analyses we obtained standardized amounts of erinacine A and hericenones C and D in H. erinaceus extracts, that were tested in our animal model of physiological aging. Two-month oral supplementation with H. erinaceus reversed the age-decline of recognition memory. Proliferating cell nuclear antigen (PCNA) and doublecortin (DCX) immunohistochemistry in the hippocampus and cerebellum in treated mice supported a positive effect of an H. erinaceus on neurogenesis in frail mice.

Frailty is a geriatric syndrome associated with both locomotor and cognitive decline, typically linked to chronic systemic inflammation, i.e., inflammaging. In the current study, we investigated the effect of a two-month oral supplementation with standardized extracts of H. erinaceus, containing a known amount of Erinacine A, Hericenone C, Hericenone D, and L-ergothioneine, on locomotor frailty and cerebellum of aged mice. Locomotor performances were monitored comparing healthy aging and frail mice. Cerebellar volume and cytoarchitecture, together with inflammatory and oxidative stress pathways, were assessed focusing on senescent frail animals. H. erinaceus partially recovered the aged-related decline of locomotor performances. Histopathological analyses paralleled by immunocytochemical evaluation of specific molecules strengthened the neuroprotective role of H. erinaceus able to ameliorate cerebellar alterations, i.e., milder volume reduction, slighter molecular layer thickness decrease and minor percentage of shrunken Purkinje neurons, also diminishing inflammation and oxidative stress in frail mice while increasing a key longevity regulator and a neuroprotective molecule. Thus, our present findings demonstrated the efficacy of a non-pharmacological approach, based on the dietary supplementation using H. erinaceus extract, which represent a promising adjuvant therapy to be associated with conventional geriatric treatments.

Brain aging is a crucial risk factor for several neurodegenerative disorders and dementia. The most affected cognitive function is memory, worsening early during aging. Inflammation and oxidative stress are known to have a role in pathogenesis of cognitive impairments, and a link exists between aging/frailty and immunosenescence/inflammaging. Based on anti-aging properties, medicinal mushrooms represent a source to develop medicines and functional foods. In particular, Hericium erinaceus (He) displays several actions ranging from boosting the immune system to fighting senescence, due to its active ingredients/metabolites. Among these, Ergothioneine (ERGO) is known as the longevity vitamin. Currently, we demonstrated the efficacy of an ERGO-rich He primordium extract (He2) in preventing cognitive decline in a murine model of aging. We focused on recognition memory deterioration during aging, monitored through spontaneous behavioral tests assessing both memory components and frailty index. A parallel significant decrease in key markers of inflammation and oxidative stress, i.e., IL6, TGFβ1, GFAP, Nrf2, SOD1, COX2, NOS2, was revealed in the hippocampus by immunohistochemistry, accompanied by an enhancement of NMDAR1and mGluR2, crucially involved in glutamatergic neurotransmission. In summary, we disclosed a selective, preventive and neuroprotective effect of He2 on aged hippocampus, both on recognition memory as well on inflammation/oxidative stress/glutamate receptors expression.

Phenotypic frailty is characterized by a progressive decline in physical functioning. During ageing, morphological and functional alterations involve the brain, and chief theories involve oxidative stress, free radical accumulation, and reduced antioxidant defenses as the most implicated mechanisms. From boosting the immune system to fighting senescence, medicinal mushrooms have been found to have a number of health and longevity benefits. Among them, Hericium erinaceus (He) has been demonstrated to display a variety of physiological effects, including anti-aging properties. Thus, He represents an attractive natural source for developing novel medicines and functional foods, based on the identification of its active ingredients and metabolites. Particularly, H. erinaceus primordium (He2) extract contains a high amount of Ergothioneine (ERGO), the longevity vitamin. Herein, we revealed the preventive effect of ERGO-rich He2 extract in a preclinical model, focusing on locomotor decline during ageing monitored through spontaneous behavioral test. This effect was accompanied by a significant decrease in some oxidative stress markers (NOS2, COX2) paralleled by an increase in P53, showed in cerebellar cortex cells and fibres by immunohistochemistry. In summary, we demonstrated the neuro-protective and preventive effects of He2 extract during aging, probably due to its peculiarly high ERGO content.

Although medicinal mushroom extracts have been proposed as promising anti-cancer agents, their precise impacts on metastatic breast cancer are still to be clarified. For this purpose, the present study exploited the effect of a novel medicinal mushroom blend, namely Micotherapy U-care, in a 4T1 triple-negative mouse breast cancer model. Mice were orally administered with Micotherapy U-care, consisting of a mixture of Agaricus blazei, Ophiocordyceps sinensis, Ganoderma lucidum, Grifola frondosa, and Lentinula edodes. The syngeneic tumor-bearing mice were generated by injecting 4T1 cells in both supplemented and non-supplemented mice. After sacrifice 35 days later, specific endpoints and pathological outcomes of the murine pulmonary tissue were evaluated. (i) Histopathological and ultrastructural analysis and (ii) immunohistochemical assessment of TGF-ß1, IL-6 and NOS2, COX2, SOD1 as markers of inflammation and oxidative stress were performed. The QoL was comparatively evaluated. Micotherapy U-care supplementation, starting before 4T1 injection and lasting until the end of the experiment, dramatically reduced the pulmonary metastases density, also triggering a decrease of fibrotic response, and reducing IL-6, NOS, and COX2 expression. SOD1 and TGF-ß1 results were also discussed. These findings support the valuable potential of Micotherapy U-care as adjuvant therapy in the critical management of triple-negative breast cancer.

Ageing is a biological phenomenon that determines the impairment of cognitive performances, in particular, affecting memory. Inflammation and cellular senescence are known to be involved in the pathogenesis of cognitive decline. The gut microbiota–brain axis could exert a critical role in influencing brain homeostasis during ageing, modulating neuroinflammation, and possibly leading to inflammaging. Due to their anti-ageing properties, medicinal mushrooms can be utilised as a resource for developing pharmaceuticals and functional foods. Specifically, Hericium erinaceus (He), thanks to its bioactive metabolites, exerts numerous healthy beneficial effects, such as reinforcing the immune system, counteracting ageing, and improving cognitive performance. Our previous works demonstrated the capabilities of two months of He1 standardised extract oral supplementation in preventing cognitive decline in elderly frail mice. Herein, we showed that this treatment did not change the overall gut microbiome composition but significantly modified the relative abundance of genera specifically involved in cognition and inflammation. Parallelly, a significant decrease in crucial markers of inflammation and cellular senescence, i.e., CD45, GFAP, IL6, p62, and γH2AX, was demonstrated in the dentate gyrus and Cornus Ammonis hippocampal areas through immunohistochemical experiments. In summary, we suggested beneficial and anti-inflammatory properties of He1 in mouse hippocampus through the gut microbiome–brain axis modulation.