METHODS FOR ENHANCING VASCULAR DENSITY
The present invention relates to methods of increasing vascular density and/or blood flow in tissue of a subject, and to increasing exercise capacity of a subject, the methods include administering to a subject an effective amount of an agent that elevates SIRT1 activity in endothelial cells of the subject, the invention further includes administering an NAD+ agonist or NAD+ precursor to a subject to increase vascular density and/or blood flow. The invention includes compositions comprising the said agent.
1 . A method of increasing vascular density and/or blood flow and/or angiogenesis and/or neovascularisation in tissue of a subject, and/or exercise capacity of a subject, comprising administering to the subject an effective amount of an agent which elevates SIRT1 activity or SIRT1 expression in endothelial cells of the subject.
2 - 9 . (canceled)
10 . The method of claim 1 , wherein increasing vascular density and/or blood flow in tissue of a subject, and/or increasing exercise capacity in a subject, comprises:
(a) subjecting the subject to exercise training over an exercise training period; and
(b) administering to the subject an effective amount of an agent which elevates SIRT1 activity or SIRT1 expression in endothelial cells of the subject before and/or during the exercise training period.
11 . The method of claim 10 , wherein the agent is an NAD+ precursor before and/or during the exercise training period.
12 - 13 . (canceled)
14 . The method of claim 10 , wherein the NAD + agonist is an agent which raises NAD + levels in endothelial cells of the subject.
15 . The method of claim 14 , wherein the agent which raises NAD + levels in an endothelial cell of the subject comprises an NAD + precursor.
16 . The method of claim 15 , wherein the NAD+ precursor is NMN or a pharmaceutically acceptable salt thereof, NR or a pharmaceutically acceptable salt thereof, NaR or a pharmaceutically acceptable salt thereof, NAAD or a pharmaceutically acceptable salt thereof, or NaMN or a pharmaceutically acceptable salt thereof.
17 . The method of claim 1 , wherein the agent is administered in combination with a H 2 S precursor.
18 - 19 . (canceled)
20 . The method of claim 17 , wherein the H 2 S precursor is sodium hydrosulfide, or a pharmaceutically acceptable salt thereof, or GYY4137 or a pharmaceutically acceptable salt thereof.
21 . The method of claim 1 , wherein the increase in vascular density is an increase in microvascular density and/or an increase in capillary density.
22 . (canceled)
23 . The method of claim 1 , wherein the tissue is muscle.
24 . (canceled)
25 . The method of claim 1 , wherein the subject is an aged subject.
26 . The method of claim 1 , wherein the agent, NAD+ agonist or NAD+ precursor is administered orally.
27 . A method of treating or preventing a disease or condition selected from the group consisting of: coronary and/or peripheral arterial disease; ischaemia; ulcers; lung disease; pulmonary hypertension; frailty; sarcopenia; neurodegenerative disease, such as vascular dementia; stroke; haemorrhage; osteoporosis; heart disease; and vascular disease, in a subject, comprising administering to the subject an effective amount of an agent which elevates SIRT1 activity or SIRT1 expression in endothelial cells of the subject.
28 - 40 . (canceled)
41 . A method of:
increasing vascular density in tissue of a subject having reduced mobility;
increasing exercise capacity in subjects having reduced mobility;
enhancing liver sinusoidal endothelial cell function in a subject;
enhancing the physical performance of a subject;
enhancing the effects of exercise in a subject;
improving vascular recovery in a subject following injury or immobilisation;
enhancing benefits of physiotherapy in a subject;
increasing endurance in a subject;
enhancing blood flow to the eyes of a subject;
enhancing skin appearance of a subject;
increasing vitality of an aged subject
enhancing meat production in an animal; or
enhancing the performance of a racing animal,
comprising administering to the subject an effective amount of an NAD + agonist.
42 . The method of claim 41 , wherein the NAD+ agonist is an NAD+ precursor.
43 . (canceled)
44 . A composition for increasing vascular density and/or blood flow and/or exercise capacity in a subject, comprising an NAD+ precursor and optionally a H 2 S precursor.
45 . A virus comprising a viral vector, wherein the viral vector comprises nucleic acid for increasing vascular density and/or blood flow in tissue of a subject, and/or exercise capacity of a subject, wherein the nucleic acid comprises a coding sequence which encodes:
(a) SIRT1 protein;
(b) one or more NAD+ biosynthetic enzymes, or
(c) an NAMPT, NMNAT1, NMNAT2, and/or NMNAT3 miRNA antagonist.
46 - 52 . (canceled)
53 . The method of claim 41 , wherein the method is for increasing vitality of an aged subject, and the subject is a companion animal or pet.
54 - 56 . (canceled)
57 . A method of reducing:
(a) lack of coordination;
(b) extreme fatigue and lethargy;
(c) loss of appetite;
(d) decline or worsening of an existing condition;
(e) slow healing of wounds; or
(f) the onset of age-related diseases,
in an aged subject, comprising administering to the subject an effective amount of an NAD precursor.
58 - 59 . (canceled)
60 . The method of claim 53 , wherein the aged subject is a dog.
61 . The method of claim 1 , wherein the subject is a human.
62 . The method of claim 1 , wherein the subject is a non-human.
63 . The method of claim 27 , wherein the agent comprises an NAD + precursor.
64 . The method of claim 27 , wherein the agent is administered in combination with a H 2 S precursor.