Every claim, sourced.
Each numbered superscript on this site links here. Every entry states what it supports, what kind of evidence it is, and where it is cited, with a link to the original publication.
Population figures
- 1Population survey
42.2% of US adults 30 and older have periodontitis; 59.8% of adults 65 and older.
Eke PI, Thornton-Evans GO, Wei L, Borgnakke WS, Dye BA, Genco RJ. Periodontitis in US adults: National Health and Nutrition Examination Survey 2009–2014. J Am Dent Assoc. 2018;149(7):576–588.
- 2Economic estimate
An estimated 29.4 million US adults have obstructive sleep apnea; about 80% are undiagnosed.
Frost & Sullivan, commissioned by the American Academy of Sleep Medicine. Hidden Health Crisis Costing America Billions: the economic burden of obstructive sleep apnea. AASM; 2016.
- 3Reference database
The mouth hosts roughly 700 bacterial species, catalogued in the Human Oral Microbiome Database.
Dewhirst FE, Chen T, Izard J, et al. The human oral microbiome. J Bacteriol. 2010;192(19):5002–5017.
Oral bacteria and systemic disease
- 4Association
DNA of periodontal pathogens, including P. gingivalis, was detected in human carotid atheromatous plaque.
Haraszthy VI, Zambon JJ, Trevisan M, Zeid M, Genco RJ. Identification of periodontal pathogens in atheromatous plaques. J Periodontol. 2000;71(10):1554–1560.
- 5Association + animal mechanism
Gingipains from P. gingivalis were found in Alzheimer's brain tissue and correlated with tau and ubiquitin; oral infection in mice led to brain colonization.
Dominy SS, Lynch C, Ermini F, et al. Porphyromonas gingivalis in Alzheimer's disease brains: evidence for disease causation and treatment with small-molecule inhibitors. Sci Adv. 2019;5(1):eaau3333.
- 6Association
Fusobacterium sequences are enriched in colorectal tumors compared with adjacent normal tissue.
Kostic AD, Gevers D, Pedamallu CS, et al. Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome Res. 2012;22(2):292–298.
- 7Mechanistic
The FadA adhesin of F. nucleatum binds E-cadherin and activates β-catenin signaling that promotes tumor growth.
Rubinstein MR, Wang X, Liu W, Hao Y, Cai G, Han YW. Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/β-catenin signaling via its FadA adhesin. Cell Host Microbe. 2013;14(2):195–206.
- 8Prospective
Carriage of P. gingivalis and A. actinomycetemcomitans in oral samples was associated with higher subsequent risk of pancreatic cancer.
Fan X, Alekseyenko AV, Wu J, et al. Human oral microbiome and prospective risk for pancreatic cancer: a population-based nested case-control study. Gut. 2018;67(1):120–127.
- 9Randomized trial
Intensive periodontal treatment improved endothelial (blood-vessel lining) function at six months.
Tonetti MS, D'Aiuto F, Nibali L, et al. Treatment of periodontitis and endothelial function. N Engl J Med. 2007;356(9):911–920.
- 10Mechanistic
P. gingivalis carries an enzyme that citrullinates human proteins, the targets of autoantibodies in rheumatoid arthritis.
Wegner N, Wait R, Sroka A, et al. Peptidylarginine deiminase from Porphyromonas gingivalis citrullinates human fibrinogen and α-enolase: implications for autoimmunity in rheumatoid arthritis. Arthritis Rheum. 2010;62(9):2662–2672.
- 11Mechanistic + association
The leukotoxin of A. actinomycetemcomitans triggers hypercitrullination in neutrophils; exposure was associated with rheumatoid arthritis.
Konig MF, Abusleme L, Reinholdt J, et al. Aggregatibacter actinomycetemcomitans–induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis. Sci Transl Med. 2016;8(369):369ra176.
- 12Case report
A single documented case in which an oral strain of F. nucleatum was traced to a term stillbirth.
Han YW, Fardini Y, Chen C, et al. Term stillbirth caused by oral Fusobacterium nucleatum. Obstet Gynecol. 2010;115(2 Pt 2):442–445.
- 13Review
Diabetes raises periodontitis risk, and periodontitis worsens glycemic control: a bidirectional relationship.
Preshaw PM, Alba AL, Herrera D, et al. Periodontitis and diabetes: a two-way relationship. Diabetologia. 2012;55(1):21–31.
Breath, nitric oxide and sleep
- 14Human physiology
The paranasal sinuses produce high concentrations of nitric oxide, carried with nasal airflow.
Lundberg JO, Farkas-Szallasi T, Weitzberg E, et al. High nitric oxide production in human paranasal sinuses. Nat Med. 1995;1(4):370–373.
- 15Human intervention
Antiseptic mouthwash reduced oral nitrate-to-nitrite conversion and raised blood pressure in healthy volunteers.
Kapil V, Haydar SMA, Pearl V, Lundberg JO, Weitzberg E, Ahluwalia A. Physiological role for nitrate-reducing oral bacteria in blood pressure control. Free Radic Biol Med. 2013;55:93–100.
- 16Observational
Mouth breathing during sleep was associated with lower intraoral pH.
Choi JE, Waddell JN, Lyons KM, Kieser JA. Intraoral pH and temperature during sleep with and without mouth breathing. J Oral Rehabil. 2016;43(5):356–363.
- 17Systematic review
Reviews the evidence linking sleep bruxism with obstructive sleep apnea and airway events.
Relationship between bruxism and obstructive sleep apnea: a systematic review of the literature. 2025. PubMed Central PMC12295005.
- 18Clinical guideline
Oral appliance therapy is recommended for adults with obstructive sleep apnea who do not tolerate CPAP or prefer an alternative.
Ramar K, Dort LC, Katz SG, et al. Clinical practice guideline for the treatment of obstructive sleep apnea and snoring with oral appliance therapy: an update for 2015. J Clin Sleep Med. 2015;11(7):773–827.
- 19Animal study
Forced oral breathing in growing primates altered facial and dental-arch development.
Harvold EP, Tomer BS, Vargervik K, Chierici G. Primate experiments on oral respiration. Am J Orthod. 1981;79(4):359–372.
Healing, bone and nerve
- 20Review
Healing proceeds through overlapping hemostasis, inflammation, proliferation and remodeling phases; systemic factors such as stress and diabetes impair it.
Guo S, DiPietro LA. Factors affecting wound healing. J Dent Res. 2010;89(3):219–229.
- 21Review
Osseointegration is a cell-driven biological healing process, not only a mechanical fit.
Terheyden H, Lang NP, Bierbaum S, Stadlinger B. Osseointegration: communication of cells. Clin Oral Implants Res. 2012;23(10):1127–1135.
- 22Review
Inferior alveolar and lingual nerve injuries are classified by severity, and timely evaluation and referral affect recovery.
Ziccardi VB, Zuniga JR. Nerve injuries after third molar removal. Oral Maxillofac Surg Clin North Am. 2007;19(1):105–115.
Aging and longevity
- 23Animal study
Clearance of metabolic waste, including β-amyloid, from the brain increases during sleep.
Xie L, Kang H, Xu Q, et al. Sleep drives metabolite clearance from the adult brain. Science. 2013;342(6156):373–377.
- 24Review
Chronic low-grade inflammation (inflammaging) is a shared driver of age-related disease.
Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A. Inflammaging: a new immune–metabolic viewpoint for age-related diseases. Nat Rev Endocrinol. 2018;14(10):576–590.
- 25Review
Defines the hallmarks of aging, including chronic inflammation and dysbiosis.
López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: an expanding universe. Cell. 2023;186(2):243–278.
Regulatory
- 26Regulatory source
The current FDA status of bulk substances, including peptides, used in pharmacy compounding.
U.S. Food and Drug Administration. Bulk drug substances used in compounding under section 503A of the FD&C Act. Updated periodically.
Association is not causation. Where a link rests on correlation, a single case, animal work or laboratory mechanism, it is labeled that way, and the book does the same. This list is a summary for readers; the book's Notes section carries the complete apparatus.
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