PROTEOSTASIS. Defines the ability of the body to maintain the fidelity of biogenesis of protein (non-defective proteins), folding. movement, and removal of old protein aggregates. Especially significant is the removal of old damaged protein aggregates, which are detrimental to the functioning of the cell. Clearing old cellular debris, through a process called autophagy, greatly enhances the youthful functioning of the cell.
CURCUMIN ENHANCES AUTOPHAGY. Lifespan and autophagy are strongly
associated with one another. Calorie restriction, resveratrol and curcumin are known to improve autophagy and increase lifespan. In fact, all life extension mechanisms depend upon the importance of autophagy for clearing cellular damage.(1,2)
Aging affects molecular pathways that influence health and longevity. As a result, there is a reduction of cellular debris clearance (autophagy), decreased the pool of stem cells, increase in inflammation and cellular senescence.
CURCUMIN has been shown to by positively regulate longevity by through important molecular pathways, including IIS, mTOR and FOXO. Curcumin is a powerful activator of the body's antioxidant defense system, as an Nrf2 activator. As an antioxidant, curcumin stabilizes and protects telomeres. Inflammation is also a powerful promoter of aging. Curcumin inhibits the powerful inflammation transcription factor NF-κB and is associated with reduced levels of inflammation.(3) PROTEOSTASIS is impacted by all these aging pathways.(4) Therefore, curcumin supports longevity via aging signaling and proteostasis (autophagy).
Misfolded proteins in the brain are associated with poorly functioning autophagy. Autophagy removes aggregate protein accumulations which is responsible for neurodegeneration. Curcumin, research indicates, may help restore autophagy in the brain, to clear these misfolded proteins. (5) Oleuropein, a component of Olive Oil, in addition to curcumin, is implicated in mitophagy in the brain, removing old and dysfunction mitochondria. (6)
SIRT1 is an enzyme which regulates cellular processes relative to longevity. SIRT1 INCREASES PROTEOSTASIS ,which is an important component of the longevity effect. Natural activators of SIRT1 include Curcumin, Fisetin, Quercetin and Resveratrol.(15)
Cardiac remodeling through failure of autophagy, proteostasis and inflammation are believed to be a root cause of atrial fibrillation. Cardiomyocytes are replaced by non-functional proteins..(12. 13)
With age, cells become replicative scenescent - losing ability to produce new cells. Furthermore, scenescent cells are old cells. Old cells have been shown to lose proteostasis, which further limit the abilty of the cell to respond to external threats and maintain function. Curcumin and pterostilbene(11) helps inhibit cellular scenescence. Fisetin and quercetin are considered senolytics, which are capable of removing scenescent cells. (10) Importantly, recent research also indicates that curcumin also removes scenescent cells.(14)
CURCUMIN PXC® - Incorporates highly bioavailable curcumin Furthermore, Curcumin PXC also includes powerful supplemental ingredients in support of proteostasis.
Protein Homeostasis is a significant determining factor in the longevity of multi-cellular animals.(1) Quality control mechanisms in place to support protein homeostasis include autophagy - the essential degradation of toxic proteins. As an organism ages, protein homeostasis is gradually lost.(2) Autophagy, by lysosomes, plays an active role in protein homeostasis, by eliminating toxic and damaged proteins such as amyloid. Nrf2 activation increases autophagy activity. Reduced levels of autophagy are tied to Alzheimers Disease. Misfolded amyloid beta and tau proteins are involved in the development of Alzheimers Disease.(11)
Autophagy is not only critical in the deposition of toxic proteins, but is functionally important in the degradation and recycling of defective cellular components. Research now indicates that autophagy is central for maximum longevity.(13)
AUTOPHAGY: FISETIN and CURCUMIN
AGING - LOSS OF PROTEOSTASIS (TOXIC PROTEINS)
(1) Alavez A, et al. Amyloid-binding compounds maintain protein homeostasis during ageing and extend lifespan. Nature. 2011 Apr
(2) Kuang H, et al, Exploring the bi-directional relationship between autophagy and Alzheimer's disease. CNS Neurosci Ther. 2019 Sep
(3) Chen T, et al. Rapamycin and other longevity-promoting compounds enhance the generation of mouse induced pluripotent stem cells. Aging Cell. 2011 Oct
(4) Yang W, et al. Fisetin improves lead-induced neuroinflammation, apoptosis and synaptic dysfunction in mice associated with the AMPK/SIRT1 and autophagy pathway. Food Chem Toxicol .2019 Sep
(5) Ahmad A, et al. Neuroprotective Effect of Fisetin Against Amyloid-Beta-Induced Cognitive/Synaptic Dysfunction, Neuroinflammation, and Neurodegeneration in Adult Mice. Mol Neurobiol. 2017 Apr
(6) Singh S, et al. Fisetin as a caloric restriction mimetic protects rat brain against aging induced oxidative stress, apoptosis and neurodegeneration. Life Sci. 2018 Jan
(7) Ziontz J, et al. Tau pathology in cognitively normal older adults. Alzheimers Dement (Amst). 2019 Sep
(8) Yousefzadeh MJ, et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018 Oct
(9) Lin C, et al. Rosmarinic acid improved antioxidant properties and healthspan via the IIS and MAPK pathways in Caenorhabditis elegans. Biofactors. 2019 Jun
(10) De Biase D, et al. Amyloid precursor protein, lipofuscin accumulation and expression of autophagy markers in aged bovine brain. BMC VET Res, 2017.
(11) Buchter C, et al. Myricetin-Mediated Lifespan Extension in Caenorhabditis elegans Is Modulated by DAF-16. Int J Mol Sci. 2913 Jun.
(12) Bielak-Zmijewsja A, et al. The Role of Curcumin in the Modulation of Ageing. Int J Mol Sci. 2019 Mar.
(13) Bareja A, et al. Maximizing Longevity and Healthspan: Multiple Approaches All Converging on Autophagy. Front Cell Dev Biol. 2019 Sep
In the field of anti-aging, the flavonoid fisetin is emerging as a potent longevity compound. Fisetin affects the aging process in experimental animals through multiple pathways, including senolytics (removing senescent cells)m SIRT1 activation, calorie restriction mimic and homeostasis.
Senolytics- the rejuvenation of the cellular environment, by eliminating senescent cells. Aging is characterized by the accumulation of senescent cells. These are cells which are irreversibly unable to grow and function and are resistant to normal cellular clearance. Senescent cells not only interfere with normal tissue functioning, but may also be toxic to neighboring cells. Fisetin, has been shown to be a potent senolytic, with the ability to eliminate senescent cells. (1)
REDOX HOMEOSTASIS / IONIC HOMEOSTASIS
SIRTUIN ACTIVATION (SIRT1)
PLURIPOTENT STEM CELLS (Induction)
PROTEOSTASIS - ABNORMAL PROTEIN ACCUMULATION / AUTOPHAGY
(1) Glossmann HH, et al, Metformin and Aging: A Review. Gerontology. 2019. Sept.
(2) Kirkland JL, et al. Cellular Scenescence. A Translational Perspective. EBioMedicine, 2017
(3) van Deursen JM. The role of Scenescent Cells in Ageing. Nature 2014.
(4) Yousefzadeh MJ, et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine, 2018
(5) Singh S, et al. Fisetin, a potential calorie restriction mimetic, attenuates senescence biomarkers in rat erythrocytes. Biochem Cell Biol. 2019 Aug
(6) Singh S, et al. Fisetin, a potential calorie restriction mimetic,modulates ionic homeostasis in senescence induced and naturally aged rats. Biochem Cell Biol. 2019 Sept.
(7) Shin-Hae Lee, et al. Sirtuin signaling in cellular senescence and aging. BMB Rep. 2019 Jan
(8) Chen T, et al. Rapamycin and other longevity-promoting compounds enhance the generation of mouse induced pluripotent stem cells. Aging Cell. 2011.
(9) Bai, et al. Small Molecules as SIRT Modulators. Mini Rev Med Chem. 2018.
(10) Zhang H, et al. Nrf2⁻ARE Signaling Acts as Master Pathway for the Cellular Antioxidant Activity of Fisetin. Molecules. 2019 Feb.
(10) Zheng W, et al. Fisetin inhibits IL-1β-induced inflammatory response in human osteoarthritis chondrocytes through activating SIRT1 and attenuates the progression of osteoarthritis in mice. Int Immunopharmacol. 2017 Apr
(11) Simunkova M, et al. Management of oxidative stress and other pathologies in Alzheimer's disease. Arch Toxicol. 2019 Aug
(12) Sunhyo K, et al. Fisetin stimulates autophagic degradation of phosphorylated tau via the activation of TFEB and Nrf2 transcription factors Sci Rep. 2016.