Circadian Rhythms are Key to Health
Aging involves multiple biological pathways acting simultaneously, and current interventions often fall short because they address only singular causes. Recent discoveries reveal that circadian rhythms, present in most cells, orchestrate essential life functions and play a crucial role in the aging process.
​
Circadian rhythms regulate nearly every aspect of aging, including bioenergetic, neurologic, and metabolic health. Disruptions to these rhythms can lead to oxidative stress, inflammation, and microbiome alterations, which are linked to various health issues such as Alzheimer’s disease, metabolic syndrome, obesity, and depression.
​
Restoring circadian function offers a promising new approach to addressing chronic conditions and promoting healthy aging. As we age, our daily rhythms often shift due to environmental factors, leading to reduced amplitude in circadian oscillations. This disruption is associated with inflammation, oxidative stress, and age-related diseases like depression, cognitive disorders, physical decline, and skin issues
Unlocking Youth:
How Circadian Rhythms and
Bioflavonoids Transform the Aging Process
Circadian Rhythm Disruptions
Accelerate Aging
Daily rhythm tends to change with age and environmental factors.
The amplitude, that is highest point of the circadian oscillation, during a 24hr cycle, shortens, with age.
​
Disrupted rhythms are linked to inflammation, oxidation, and many age-related diseases such as depression, cognition disorders, physical decline, cancer, metabolic disorder, microbiome imbalances, and skin pathogenesis.
Our Goal is to Restore Diminishing Rhythms to prevent Age -Decline
Scientists screened a quarter million compounds, to discover a promising group of compounds bioflavonoids, that bind & control clock genes to affect many biological pathways:
Anti-inflammatory, anticancer, antioxidant, neuroprotective, metabolic and cardio-protective
Unique Mechanism of Action; Binding & Controlling Clock Genes to Improve Health Markers
​
​
Aging, unhealthy. adults display dampened circadian amplitudes
+
​
​
VITAMIN P™ easily absorbs into tissues , binding to Retinoic Orphan Receptor (ROR), which regulate clock genes
+
​
​
​
Key longevity, bioenergy, immune, & metabolic targets, are subject to rhythmicity
+
Addressing Bioavailability
Most bioflavonoids have low stability, permeability and solubility, in addition to poor bioavailability, and therefore, the benefits of bioflavonoids observed in animals are difficult to achieve in humans.
A lipid-based non-toxic delivery system is combined with pharmacologically active compound PMF (ex; nobiletin) improves delivery thruough the stratum corneum layer, to reach the keratinocytes.
Upon exposure to a physiologic environment in the epidermis, the pharmacologically active compound released and elicits its therapeutic benefits.
Lipid Encapsulation Technology Transforms Citrus-Derived Flavonoids into Bioavailable Functional Substances
Addressing the Hallmarks of Aging with Chronosense
References
1. https://www.nigms.nih.gov/education/pages/factsheet_circadianrhythms.aspx. Accessed July 31, 2018
2. http://news.mit.edu/2013/the-link-between-circadian-rhythms-and-aging-0620.
3. Baron KG, Reid KJ. Circadian misalignment and health. Int Rev Psychiatry. 2014;26(2):139-54
4. Musiek ES, Holtzman DM. Mechanisms linking circadian clocks, sleep, and neurodegeneration. Science.2016;354(6315):1004-8.​
5. Hood S, Amir S. Neurodegeneration and the Circadian Clock. Front Aging Neurosci. 2017;9(170):170.
6. Scheer FA, Hilton MF, Mantzoros CS, et al. Adverse metabolic and cardiovascular consequences of circadian misalignment. Proc Natl Acad Sci U S A. 2009;106(11):4453-8
7.Thilakarathna Surangi, Rupasinghe H. Flavonoid Bioavailability and Attempts for Bioavailability Enhancement. Nutrients. 2013;5(9):3367–3387. doi: 10.3390/nu5093367.[PMC free article] [PubMed] [CrossRef] [Google Scholar] [Ref list]
8.Lin N, et al. Novel anti-inflammatory actions of nobiletin, a citrus polymethoxy flavonoid, on human synovial fibroblasts and mouse macrophages. Biochem. Pharmacol. 2003;65:2065–2071. doi: 10.1016/S0006-2952(03)00203-X.
9.Manach C., Williamson G., Morand C., Scalbert A., Rémésy C. Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am. J. Clin. Nutr. 2005;81:230S–242S.
10.Cardinali DP, Furio AM, Brusco LI. The use of chronobiotics in the resynchronization of the sleep/wake cycle. Therapeutical application in the early phases of Alzheimer's disease. Recent Pat Endocr Metab Immune Drug Discov. 2011 May;5(2):80-90. doi: 10.2174/187221411799015354. PMID: 22074583.
12.Lyall LM, Wyse CA, Graham N, Ferguson A, Lyall DM, Cullen B, Celis Morales CA, Biello SM, Mackay D, Ward J, Strawbridge RJ, Gill JMR, Bailey MES, Pell JP, Smith DJ. Association of disrupted circadian rhythmicity with mood disorders, subjective wellbeing, and cognitive function: a cross-sectional study of 91 105 participants from the UK Biobank. Lancet Psychiatry. 2018 Jun;5(6):507-514. doi: 10.1016/S2215-0366(18)30139-1. Epub 2018 May 15. PMID
14 Zelinski EL, Deibel SH, McDonald RJ. The trouble with circadian clock dysfunction: multiple deleterious effects on the brain and body. Neurosci Biobehav Rev. 2014;40:80-101.
15. Yu EA, Weaver DR. Disrupting the circadian clock: gene-specific effects on aging, cancer, and other phenotypes. Aging (Albany NY). 2011;3(5):479-93
16.Froy O. Circadian rhythms and obesity in mammals. ISRN Obes. 2012;2012:437198
22. Li JZ, Bunney BG, Meng F, et al. Circadian patterns of gene expression in the human brain and disruption in major depressive disorder. Proc Natl Acad Sci U S A. 2013;110(24):9950-5.
23.He B, Nohara K, Park N, et al. The Small Molecule Nobiletin Targets the Molecular Oscillator to Enhance Circadian Rhythms and Protect against Metabolic Syndrome. Cell Metab. 2016;23(4):610-21
24.Turek FW, Joshu C, Kohsaka A, Lin E, Ivanova G, McDearmon E, Laposky A, Losee-Olson S, Easton A, Jensen DR, Eckel RH, Takahashi JS, Bass J. Obesity and metabolic syndrome in circadian Clock mutant mice. Science. 2005 May 13;308(5724):1043-5. doi: 10.1126/science.1108750. Epub 2005 Apr 21. PMID: 15845877; PMCID: PMC3764501.
25.Hood, Suzanne & Amir, Shimon. (2017). The aging clock: Circadian rhythms and later life. Journal of Clinical Investigation. 127. 437-446. 10.1172/JCI90328.
26. Chen Z, Yoo SH, Park YS, et al. Identification of diverse modulators of central and peripheral circadian clocks by high-throughput chemical screening. Proc Natl Acad Sci U S A. 2012;109(1):101-6 7.
27. He B, Nohara K, Park N, et al. The Small Molecule Nobiletin Targets the Molecular Oscillator to Enhance Circadian Rhythms and Protect against Metabolic Syndrome. Cell Metab. 2016;23(4):610-21.
28.Zhang M , Zhu S , Yang W , Huang Q , Ho CT . The biological fate and bioefficacy of citrus flavonoids: bioavailability, biotransformation, and delivery systems. Food Funct. 2021 Apr 21;12(8):3307-3323. doi: 10.1039/d0fo03403g. Epub 2021 Mar 18. PMID: 33735339.
30. Nakajima A, Ohizumi Y. Potential Benefits of Nobiletin, A Citrus Flavonoid, against Alzheimer's Disease and Parkinson's Disease. Int J Mol Sci. 2019 Jul 10;20(14):3380. doi: 10.3390/ijms20143380. PMID: 31295812; PMCID: PMC6678479
31.Lee YS, Cha BY, Choi SS, Choi BK, Yonezawa T, Teruya T, Nagai K, Woo JT. Nobiletin improves obesity and insulin resistance in high-fat diet-induced obese mice. J Nutr Biochem. 2013 Jan;24(1):156-62. doi: 10.1016/j.jnutbio.2012.03.014. Epub 2012 Aug 13. PMID: 22898571.
32.Choi Y., Kim Y., Ham H., Park Y., Jeong H.S., Lee J. Nobiletin suppresses adipogenesis by regulating the expression of adipogenic transcription factors and the activation of AMP-activated protein kinase (AMPK) J. Agric. Food Chem. 2011;59:12843–12849. doi: 10.1021/jf2033208
33.14. Kanda K., Nishi K., Kadota A., Nishimoto S., Liu M.C., Sugahara T. Nobiletin suppresses adipocyte differentiation of 3T3-L1 cells by an insulin and IBMX mixture induction. Biochim. Biophys. Acta. 2012;182:461–468. doi: 10.1016/j.bbagen.2011.11.015
34.Kou, G, Li, P, Hu, Y, et al. Nobiletin activates thermogenesis of brown and white adipose tissue in high-fat diet-fed C57BL/6 mice by shaping the gut microbiota. The FASEB Journal. 2021; 35:e21267. https://doi.org/10.1096/fj.202002197R
35.Brown, S. A., Pagani, L., Cajochen, C. & Eckert, A. Systemic and cellular reflections on ageing and the circadian oscillator: a mini-review. Gerontology 57, 427–434 (2011).
36.Manoogian, E. N. C. & Panda, S. Circadian rhythms, time-restricted feeding, and healthy aging. Ageing Res Rev. 39, 59–67 (2017)
37.Sato, S. et al. Circadian reprogramming in the liver identifies metabolic pathways of aging. Cell170, 664–677 e611 (2017)
38.Banks, G., Nolan, P. M. & Peirson, S. N. Reciprocal interactions between circadian clocks and aging. Mamm. Genome 27, 332–340 (2016)
39.Takahashi, J. S. Transcriptional architecture of the mammalian circadian clock. Nat. Rev. Genet.18, 164–179 (2017)
40.Dibner C, Schibler U, Albrecht U. The mammalian circadian timing system: organization and coordination of central and peripheral clocks. Annu Rev Physiol. 2010;72:517–549. [PubMed] [Google Scholar] [Ref list
41 Zhang R, Lahens NF, Ballance HI, Hughes ME, Hogenesch JB. A circadian gene expression atlas in mammals: implications for biology and medicine. Proceedings of the National Academy of Sciences of the United States of America. 2014;111:16219–16224
42.Yang X, Downes M, Yu RT, Bookout AL, He W, Straume M, Mangelsdorf DJ, Evans RM. Nuclear receptor expression links the circadian clock to metabolism. Cell. 2006;126:801–810
42.Chen Z, Yoo SH, Takahashi JS. Small molecule modifiers of circadian clocks. Cell Mol Life Sci. 2013;70:2985–2998.