Longevity Enhancement Induced by Repetitive Injections of Botulinum Toxin (Centurion Effect)

Abstract

Described herein is a novel application involving the use of therapeutic or cosmetic formulations of botulinum toxin involving an increase and enhancement of longevity in human subjects. The inventors are physicians who have used this agent for the past 30 years for many indications and has treated a large number of patients for periods of 20-30 years, many over the age of 60 at therapy initiation for medical and aesthetic conditions. A substantial number seemed to be surviving longer than untreated patients using US census statistics. Compared to social security survival curve established over the last decade, this patient group demonstrated substantial greater longevity than the national average. Because the first remarkable patients were a group exceeding or approaching 100 years of age, the phenomenon has been termed the “centurion effect.” The physiology of this effect most likely relates to the effect botulinum has on central nervous system, circadian function, sleep synchronization, mitigation of the deterioration of age related diurnal central nervous system functions, and metabolic alterations associated with the toxins effect on brainstem circadian centers.

Claims

1. A method of statistically increasing the chances of longevity in human by the administration of a botulinum toxin a. selecting a patient; and b. administering the botulinum toxin to the patient; thereby increasing longevity in the patient.

2. The method of claim 1, wherein the botulinum toxin includes botulinum type A1-A5, B,C,D,E,F or G.

3. The method of claim 1, wherein the botulinum toxin is is injected into the face, head or neck.

4. The method of claim 1, wherein the botulinum toxin which involves the application of cream, ointment or lotion to head and neck or face or periocular region.

5. The method of claim 1, in which the patient is injected with between 1-3000 LD 50 units of botulinum toxin type A.

6. The method of claim 1, in which the patient is injected with between 1-40,000 units of botulinum toxin type B.

7. The method of claim 1, in which botulinum toxin is administered using aerosols to nose lungs, otic canals.

8. The method of claim 1, in which botulinum toxin is administered through repeated injections.

9. The method of claim 8, in which the repeated injections are administered at intervals between 2-52 weeks.

10. The method of claim 1, in which the selected patient is a human over 60 years old.

11. The method of claim 1, which causes at least one change in circadian function.

12. The method of claim 11, wherein the change in circadian function includes metabolic alteration in fat, sugar, or protein metabolism, and altered inflammatory response.

13. The method of claim 11, wherein the change in circadian function involves alteration in blood pressure, appetite, energy level, cognitive ability, and alertness.

14. The method of claim 12, wherein cognitive ability is increased without a diagnosis of a neuropsychiatric disease by enhancing sleep synchronization.

15. A method of decreasing the incidence of cardiovascular disease by a. administering botulinum toxin to the face or neck; and b. altering at least one physiologic function related to the circadian cycle.

16. The method of claim 15, in which a change in circadian cycle modulates and reduces hypertension.

17. A method of preserving normal cognition in aging human without a diagnosis of neuropsychiatric disease by a. administering botulinum toxin to the face or neck; and b. altering at least one physiologic function related to the circadian cycle.

18. The method of claim 17, in which the alteration of circadian function is increased sleep synchronization.

Description

EXAMPLES

Example 1

[0077] A 103 year old woman received repetitive botulinum injection for about 25 years. She notes repeat decrease in light sensitivity and has maintained a mobile, lucid cognition until this day. Botulinum injections were repeatedly given from age 85 forward at doses between 40-100 units every 6-12 weeks. She maintains a good short term memory, sleeps regularly and processes questions quite normally. There was no history of cardiovascular disease or hypertension. This patient was noted to be less anxious and sleeps better after injections.

Example 2

[0078] A 100 year old man received repeated botulinum injections for about 5 years for blepharospasm. Doses ranged from 40-80 U. He lived until 100 years old. During all follow-up visits, he was noted to maintain a good memory, ask insightful questions, and relate appreciate concerns regarding his medical condition.

Example 3

[0079] A 95 year old man received about 10 years of repeat botulinum toxin for over 10 years started at age 78. He is 95 living a reasonable existence. He has been able to actively work until almost 90 years old and support his daughter's aspirations to attend medical school after her 50.sup.th birthday. His sleep pattern was noted to be normal. This patient had no hypertension.

Example 4

[0080] A group of patient noted to be greater than 60 years old who received botulinum toxin injections repetitively for at least 5 years were retrospectively analyzed for duration of life compared to the 2007 Social security life expectation curve. Each patient needed at least 10 year follow up from initial injection. The majority of patient both living and deceased exceeded the life expectancy predicted by the census curve published in 2007. This was noted to be true both of patients deceased and those still living.

[0081] The shift of life expectancy over the average was unexpected and a novel observation, serendipitous outcome and utility of the benefits of botulinum toxin in this patient subset.

Example 5: (Retrospective Population Study)

[0082] Inventor retrospectively analyzed patient from his practice who were treated for at least 5 years with repetitive botulinum toxin injections ranging from 20-300 units per cycle and older than 60 years at the time of botulinum injection initiation. The median injection was about 50-70 units per cycle. In some injections were given in the head and neck with doses ranging from 20-400 units. The group of patients were diagnosed generally with movement diseases such as Meige syndrome (cranial facial dystonia), essential blepharospasm, hemifacial spasm, dystonia, bruxism). Each record was originated after the year 1982 and represented a cohort of patients treated for various other conditions. Each of these conditions involved injections on the face, head, or neck. More commonly injections were given in the periocular regions in one or more points (usually 4-20 points but rarely as many as 40 points). Deceased patient were included in the study as well as living. Date of death was obtained from patient record and/or internet obituary postings. No normalization was made for co existing malignant conditions. The early analysis of data is given in FIG. 1 comparing longevity to the statistical average. Note that the majority of patient were noted to live longer at the curve, both living and dead. The arrows depict patient still alive whereas the black dots indicate the deceased. A statistical analysis comparing the patient at the time of induction to a virtual person with longevity predicted by the 2007 census and categorical comparisons conducted using standard 1 tailed chi square. Table 1 compared the patient with a virtual longevity person (census based). Note that each bin shows a statistically significant for each grouped 5 year bin between the age of 60-65, 65-70, 70-75, 75-80, 80-85. The data in a compilation of about 61 patents. Note that as many patients are still living, the categorical comparisons will become even more significant if updated within the next several years. Further that many of the deceased occurred in prior decades than current when earlier censuses survival was reduced compared to 2007. It is noted that the average survival is increasing in the United States however the latest consensus was the reference. The inventors acknowledge there are many confounding issues using retrospective data and biases relative to cohort selection. Such biases include but not limited to committed patients, socioeconomic factors, racial factors and genetic factors, and possible genetic linkages of longevity genetic polymorphisms linking the various diseases to longevity as well as other factors. The intuition of the inventors is that the retrospective data is sufficient to formulate a targeted purposeful indication on the use of botulinum toxin as a method extending survival irrespective of mechanism.

Example 6: Use of Mammals and Demonstrating the Centurion Effect Against Shame Controls

[0083] Here, animals are enormously useful to prospectively study the effect of botulinum toxin on longevity. Animal studies have been highly effective in linking reduced food consumption with longevity as well as a number of other factors.

[0084] Here an animal population with known statistical longevity could be divided into two groups. Control cohort receiving placebo and study cohort receiving repeated non lethal injections of botulinum toxin at fixed or variable intervals. The study endpoint is death and the life duration can be analyzed under a linear or categorical statistical method. Shame or controls are used for statistical comparison using categorical or other forms of statistical analysis using probability tables (p values using a 95% or greater confidence level as a significant difference).

[0085] Additionally stresses to longevity can be applied to each study group such as a select transgenic rodent with knockout genes to circadian clock proteins regulating sleep, environmental stresses such as excess feeding, light de synchronization, or any other environmental factor causing reduced longevity. Such risk factor added environmentally or via genetic selection can be used test the effect of longevity enhancement described herein.

[0086] Further aged animals can be tested. Here it would be important to select for animals with no obvious sickness and those with no biases (selection criteria) to being inducted for study.

[0087] The expected and predicted result is the botulinum injections become a useful factor in life span preservation and enhancement.

[0088] The use of animal studies helps control against testing the notion in a prospective format controlling against biases inherent in any human study.

Example 7: Neuronal Cell Cultures

[0089] The pharmacology of the effect can be studied using neuronal cell cultures. Neurons can be harvested from animal spinal cords or brain tissues so that the effect on cell integrity and function over time can be studied. The purpose of the studies objective would be to focus on longevity and versatility of the cells to resist stress in the environment or external stress associated with cell death.

[0090] In one embodiment, the method of measuring longevity enhancement in neuronal cell cultures by virtue of injecting or applying a define amount of botulinum toxin into the cell culture; measuring the longevity of the neuronal cells to sham controls; and performing a statistical analysis between botulinum toxin treated neurons and controls.

[0091] It is anticipated that alternate cell systems can be used to study this effect.

Example 8: Improving CNS Penetration

[0092] A botulinum toxin with excipients useful for biologic membrane barrier penetration is employed to produce an enhancement in longevity. Such enhancements can include certain protein additive rich in ionic amino acid side chains, high concentration protein carriers such as albumin, poly lysine, lidocaine and associated anesthetics. The volume of the delivery injection may be increased to allow enhance central nervous system delivery.

Example 9: Prophylactic Administration Circadian Function and Longevity

[0093] A patient is treated with botulinum toxin over the face, forehead head and neck and is noted to be more alert, have a more synchronized and regular sleep, appetite, blood pressure, glucose metabolism, cortisol levels, body temperature, gastric motility and gastric hormonal function, and a lower incidence of lung, breast, and prostate cancer. The administration decreases the incidence of type 2 diabetes by synchronizing sleep, appetite and temperature with attendant changes in metabolism.

Example 10

[0094] A patient is known to have a strong family history of cardiovascular disease. Botulinum toxin is given to the face, head and neck, or periocular area by injection or topical application thereby reducing the risk of experiencing a heart attack or a lethal arrhythmia such a ventricular tachycardia leading to ventricular fibrillation. Longevity is preserved.

Example 11

[0095] A patient is known to have a strong family history of breast cancer or has a genetic makeup predisposing to breast cancer (e.g., BRCA gene positive). Botulinum toxin is given to the face, head and neck, or periocular area by injection or topical application thereby reducing the risk of experiencing breast cancer or the lethal ramifications such as metastasis leading to lung, bone and brain involvement leading to death. Longevity is preserved

Example 12

[0096] A patient is known to have either a strong family history or multiple risk factors for cardiovascular disease. Botulinum toxin is given to the face, head and neck, or periocular area by injection or topical application thereby reducing the risk of experiencing a heart attack or a lethal arrhythmia such a ventricular tachycardia leading to ventricular fibrillation. Longevity is preserved

Example 13

[0097] A patient is known to have prostate cancer. Botulinum toxin is given to the face, head and neck, or periocular area by injection or topical application thereby reducing the risk of experiencing lethal ramifications such as metastasis leading to lung, bone and brain involvement leading to death. Longevity is preserved

Example 14

[0098] A patient is known to have an increased risk of stroke based on age, other forms of cardiovascular or peripheral vascular disease, hypertension, strong family history, or previous stroke

[0099] Botulinum toxin is used to improve insomnia, sleep patterns, and circadian function synchronization thereby reducing the risk of cerebrovascular disease.

[0100] Botulinum toxin is given to the face, head and neck, or periocular area by injection or topical application thereby reducing the risk of experiencing lethal ramifications of stroke such as paralysis, impaired cognition, speech loss (aphasia, dysarthria), coma, disturbed central breathing, blindness, coordination, disorientation, seizures and death. Longevity is preserved

Examples 15

[0101] A patient is known to have a rheumatoid arthritis or is a high risk (shift worker, family history, and biologic markers-autoantibodies).

[0102] Botulinum toxin is used to improve insomnia, sleep patterns, and circadian function synchronization thereby reducing the risk of progression of rheumatoid arthritis and decrease symptoms of the disease.

[0103] Botulinum toxin is given to the face, head and neck, or periocular area by injection or topical application thereby reducing the risk of experiencing lethal ramifications such as heart failure, increased infections. Longevity is preserved

Example 16

[0104] A patient with asthma or COPD is identified with a sleep disorder or circadian defect. Botulinum toxin is used to improve insomnia, sleep patterns, and circadian function synchronization thereby reducing the risk of progression of asthma or COPD. Botulinum toxin is given to the face, head and neck, or perio ocular area by injection or topical application thereby reducing the risk of experiencing lethal ramifications of COPD or asthma such as respiratory crisis, pulmonary scarring, fibrotic lung disease, emphysema, and acidosis. Longevity is preserved