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Therapeutic intervention to mimic the effect of caloric restriction

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Title: Therapeutic intervention to mimic the effect of caloric restriction.
Abstract: Methods are provided for promoting longevity and decreasing the incidence of aging associated pathologies (e.g., cancer) by the administration of one or more of the following LFFA: linoleic, oleic and palmitic acid. Secondary LFFA derived from this set, as well as their CoA derivatives and synthetic analogs, are effective also in promoting longevity and delaying the onset of age associated disorders. In addition, interventions including LFFA and CoA LLFA formulations are described which protect the organism from acute physical stress, tissue damage and hypoxia (either due to trauma or secondary to surgical procedures. ...


Browse recent Hunton & Williams LLP Intellectual Property Department patents - Washington, DC, US
Inventor: Marco CHACON
USPTO Applicaton #: #20110046221 - Class: 514558 (USPTO) - 02/24/11 - Class 514 
Drug, Bio-affecting And Body Treating Compositions > Designated Organic Active Ingredient Containing (doai) >Radical -xh Acid, Or Anhydride, Acid Halide Or Salt Thereof (x Is Chalcogen) Doai >Carboxylic Acid, Percarboxylic Acid, Or Salt Thereof (e.g., Peracetic Acid, Etc.) >Higher Fatty Acid Or Salt Thereof

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The Patent Description & Claims data below is from USPTO Patent Application 20110046221, Therapeutic intervention to mimic the effect of caloric restriction.

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BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is directed to methods for increased longevity, delay of aging associated disorders, protection from acute physical stress and induction of regeneration and healing by administration of Long chain Free Fatty Acids (LFFA) and CoA derivatives of Long chain Free Fatty Acids (CoALFFA) in mammals.

2. Review of Related Art

Sixty years of active investigation has conclusively demonstrated that reduced caloric intake extends life span in a wide variety of animal species, including mammals (e.g., mice and rats) (Ingram, D. K. et al., “The Potential for Nutritional Modulation of the Aging Process,” Food and Nutrition Press (1991)). Moreover, the incidence of pathologies associated with aging in rodents are also delayed by caloric restriction (CR) (Roth, G. S. et al., Nature Medicine 1:414-415 (1995) and Weindruch, R., Scientific American: 46-52 (January 1996)) More recently, on-going CR studies using primates seem to mimic comparable biochemical changes observed in rodents (Roth, et al., 1995), and, by extension, the same effects should be expected to occur in humans subjected to caloric restriction.

Several hypotheses have been proposed to explain the mechanism(s) underlying the beneficial effects of CR, and some of these have been discarded. Today, it is accepted that the anti-aging effects of CR are not mediated by a retardation in growth and development, or by a reduction in body fat of animals subjected to caloric restriction. Still under investigation is the hypothesis that the beneficial effects of CR are due to a reduction in oxidative damage secondary to the generation of oxygen radicals (Weindruch, R., 1996). Support for this hypothesis is derived from studies demonstrating a reduction in lipid peroxidation and induction of the enzyme Superoxide Dismutase (Heydari, A. R. et al., Annals N.Y. Academy Science 663-384-395 (1992) and Yu, B. P., “Free Radicals in Aging” CRC Press (1993)) in animals subjected to caloric restriction. Another hypothesis that has received considerable attention attributes the beneficial effects of CR to the induction of “protective genes”. Investigators pursuing this hypothesis have demonstrated the induction of genes coding for SOD, HRP-70 and A2u-globulin and concluded that the effects of CR regulate gene expression at the transcriptional level (Heydari, A. R. et al., (1992). Most recently, using a genomics based approach to analyze gene expression in the skeletal muscles of aged and CR mice, it was proposed that CR retards the aging process by causing a metabolic shift resulting in increased protein turnover and decreased macromolecular damage (Lee, et al., 1999, Science, 285:1390-1393).

Although it is likely that protection against oxidative damage, and the induction of protective genes may play a role in the beneficial effects of CR, the underlying mechanism(s) involved remain a mystery.

SUMMARY

OF THE INVENTION

This invention provides a method for improving the health of a mammal comprising administering to the mammal a composition comprising LFFA, CoALFFA, or other LFFA analogs in an amount sufficient to (a) inhibit thyroid hormone receptor binding in vivo, (b) inhibit Na/K ATPase and Ca ATPase in vivo, (c) conserve energy fuels, (d) reduce oxygen consumption in vivo, (e) cause a decrease in core body temperature in said mammal, and/or (f) activation of protective genes in, vivo. The protective genes include p53, SOD, α-2-globulin, and/or HSP-70. Suitable mammals include livestock, household pets, and especially humans. Preferred analogs of LFFA have enhanced half-lives in the circulation in the mammal. In preferred embodiments of this method, angiogenesis in the mammal is decreased, and/or hypoxia tolerance in the mammal is enhanced. This invention also, provides compositions comprising LFFA, CoALFFA, or other LFFA analogs formulated for administering according to the method of this invention.

In one embodiment of this invention, the method comprises administering LFFA, CoALFFA, or other LFFA analogs to a human anticipating surgery, and the administration is carried out prior to surgery. In an alternative embodiment, the method comprises administering LFFA, CoALFFA, or other LFFA analogs to a mammal suffering from a condition characterized by hypoxia or an increased risk of local or systemic hypoxia.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic representation of the Single Mediator Hypothesis.

FIG. 2 shows that LFFAs inhibit thyroid hormone synthesis in vitro, as shown by the effect of in vitro free fatty acids on 5′ deiodinase activity as a function of substrate concentration. Reaction velocities were measured under control conditions (▴) and in the presence of 1 mM free fatty acids: palmitic acid () and oleic acid (▪). Each point on the curve represents the mean of triplicate determinations. Lineweaver-Burk plots described lines characterized by r2 from 0.988-0.999.

FIG. 3 show that CoA-LFFAs inhibit T3 receptor binding, as demonstrated by the effect of oleoyl CoA on kinetic parameters (dissociation constant, Kd, and maximum binding, MBC). The Kd and MBC were obtained from Scatchard analysis of standard competition experiments in the presence and absence of 5 μM concentrations of oleoyl CoA. Values are the average of duplicate determinations.

DETAILED DESCRIPTION

OF THE EMBODIMENTS

The present invention relates to the use of LFFAs and CoALFFAs, either singly or in combination, to be provided either orally (as dietary supplements) or in pharmaceutical carriers (e.g., as slow-release implantables) to increase life span and to reduce the incidence and/or to delay the onset of pathologies associated with aging. The inventor has discovered that LFFAs and CoALFFAs mediate the increase in life expectancy and the reduction in aging associated disorders observed with caloric restriction, in mammals. Moreover, the inventor has established that treatment of ad-libitum fed animals with LFFAs and CoALFFAs increases their life span and reduces the incidence of age associated disorders to rates comparable to those observed in calorie restricted animals. Apparently, LFFAs and CoALFFAs function as stress signals that trigger a stress/protective response, i.e., a series of protective mechanisms including: efficient utilization of alternate fuels, reduction in oxygen consumption, prevention of oxidative tissue damage, induction of heat shock proteins, activation of the cell cycle (promoting tissue regeneration and healing), as well as induction of DNA repair and anti-tumor genes.

Rationale of the Invention

While not wishing to be bound to any particular theory which might limit the scope of the present embodiment, the inventor has developed the following rationale for the present invention to explain and expand the observations. This rationale is based on the definition of CR as a form of mild to moderate starvation. Darwinian principles are the foundation of the logic employed that led to the present invention through the elucidation of metabolic and molecular mechanisms underlying the health benefits associated with CR.

The survival of all species, including the human animal, has depended on the ability to respond quickly to external challenges that compromise the biochemical integrity and life of the organism. In the wild, when a species is threatened by injury, disease or starvation, there is a built-in wisdom in nature that enables the organism to unleash biochemical signals that are involved in the conservation of energy fuels, in mounting an immune response, in cell cycle activation and tissue repair. Assuming a non-lethal event (whether injury, infectious disease or famine), eventually, the affected animal heals, or the disease runs its course, or food becomes plentiful once again, and the organism regains its health. The organism manages to survive in the absence of any medical intervention. Moreover, a benefit (survival and restored health) is harnessed from an apparent deficit. Therefore, against the conventional wisdom, we have to consider the following paradox: It appears that it is during episodes of catabolic stress that an animal is best suited to survive, to regenerate and to heal.

In this context: chronic CR may be perceived by the organism as a threat to its survival. CR is in biochemical terms a catabolic stress which, nonetheless, marshals several positive and protective mechanisms, including: 1) Blocking of thyroid hormone expression with a consequent reduction in oxygen consumption and the formation of harmful oxygen radicals, as well as conservation of energy fuels. 2) Inhibition of high energy ion channels (ATPases). 3) Induction of protective genes generating a powerful immune response. Therefore, the calorie restricted animal is better suited to survive injuries and to recover faster from disease. The net effect is a decrease in the incidence of ailments associated with aging and an overall slow-down of the aging process.

The present invention relates to factors involved in mediating the protective effects of CR, and the inventor\'s discovery of these factors was based on the premise that such factors would have to be selectively released during catabolic stress (potential candidates therefore included hormones, second messengers, intermediary metabolites, co-factors, etc.). In mammals, the sympatho-adrenal axis is activated in response to injury, disease, or starvation, resulting in the release of stress hormones (glucocorticoids and catecholamines) which together with low insulin-glucagon ratios promote increased levels of cAMP (Axelrod, J. et al., Science 224:452-459 (1984)). The resulting metabolic changes are swift and profound. Thyroid hormone levels are decreased, resulting in a condition often referred to as Euthyroid Sick Syndrome, that is, low thyroid hormones in the absence of clinical hypothyroidism (Wartofsky, L. et al., Endocrine Review 3:164-217 (1982)). Bioactive proteins (cytokines, lymphokines and growth factors) through complex signal transduction pathways, mediate gene expression resulting in cell cycle activation, tissue regeneration and restored health (Pardee, A. B., Science 246:603-608 (1989) and Laskey, R. A. et al., Science 246:609-614 (1989)). In view of the nature of CR, the inventor was able to focus on the effects of catabolic stress on energy metabolism. In calorie restriction (as well as during catabolic stress in general), lipolysis, ketdgenesis and gluconeogenesis are favored over glycolysis and lipogenesis (Fain, J. M., et al., Adv. Exper. Med. Biol. 111:43-77 (1976)). Secondary to β-adrenergic stimuli, elevated levels of cAMP cause an activation of hormone sensitive lipase resulting in an immediate release of specific long chain free fatty acids from depot fat, including: Linoleic, oleic, and palmitic acids. These free fatty acids are increased in the circulation and in tissues where they are readily coupled to Coenzyme A (Seitz, H. J. et al., Diabetes 26:1159-1174 (1977)).

Observed Effects of Free Fatty Acids

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stats Patent Info
Application #
US 20110046221 A1
Publish Date
02/24/2011
Document #
12902357
File Date
10/12/2010
USPTO Class
514558
Other USPTO Classes
514653
International Class
/
Drawings
6


Hypoxia
Longevity
Trauma


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