Scientists think that Nerve Growth Factor plays an important role in cognitive function, mood, inflammation & more. Learn about the proposed effects of NGF & factors that may increase it.
What is Nerve Growth Factor?
Overview
Science now accepts that the brain continues to reorganize itself and create new brain cells throughout life. The birth of new neurons in the brain is referred to as neurogenesis.
Nerve growth factor (NGF) is one of a group of small protein-like molecules called neurotrophins (BDNF is another) that are responsible for neurogenesis or the development of new neurons and for the health and maintenance of mature ones.
Based on animal findings, researchers consider that NGF may promote the growth, maintenance, and survival of neurons and axons. It’s also thought to help repair the myelin sheath, which is the insulating coating around the axons [1].
Animal experiments found that as the production of NGF decreases in the brain, the animals’ ability to form new connections and to retain and access memories becomes impaired. They believe NGF might save degenerating nerves and help restore their function, but human data are lacking [2].
Discovery & Controversy
Dr. Rita Levi-Montalcini, an Italian American neurologist, won a Nobel Prize for discovering nerve growth factor in 1996. She shared the prize with biochemist Stanley Cohen.
Some of her later claims surrounded her personality with controversy. For example, she said that she used NGF eye drops to increase her life- and health-span.
Rita did live to be a centenarian. She died in 2012, aged 103 years old. Of course, the true secret to her longevity remains unknown. As far as science is concerned, evidence is lacking to claim that NGF has lifespan-increasing properties. Plus, the safety of NGF use in humans hasn’t been established.
Do NGF Levels Matter?
Studies investigating NGF levels in people are in the early stages. Findings so far have been inconclusive. We simply don’t yet know how NGF levels relate to health and disease.
In a study of 157 normal people, NGF levels were on average 194 pg/ml. Age didn’t make a significant difference amongst the participants, but NGF was significantly lower in women (112 pg/ml) than in men (243 pg/ml) [3].
Another study found lower NGF levels in people with common, so-called Western diseases, including atherosclerosis, obesity, type 2 diabetes and metabolic syndrome [4].
On the other hand, high NGF levels are found in a number of autoimmune diseases, accompanied by increased numbers of mast cells, which produce histamine and which are also able to produce NGF [5].
Some researchers have also suggested a link between higher NGF and BDNF levels in schizophrenia. They hypothesize that neurotrophins do not always support health – as is often popularly thought [6].
It’s important to realize that NGF levels can be different in different places. For example, NGF can be measured in the blood, cerebrospinal fluid (CDF), and in specific brain regions. No correlations between these measures have yet been established, as is the case with BDNF. We also don’t know if NGF from the blood can enter the brain [7, 8].
Far more NGF human research is needed to understand this little brain-active protein and its roles.
Proposed Health Effects of NGF
Caveats & Limitations
This section explores associations between NGF and aspects of health.
The majority of studies covered in this article deal with associations only, which means that a cause-and-effect relationship hasn’t been established.
For example, just because mood problems have been linked with low NGF in certain brain areas doesn’t mean that mood disorders are caused by low NGF. Nor does it mean that increasing NGF will improve mood, unless clinical data about a direct link are available. However, data are lacking to make such claims.
Additionally, even if a study did find that low brain NGF contributes to depression, NGF levels are highly unlikely to be the only causative factor. Complex mood disorders like depression always involve multiple possible factors – including brain chemistry, environment, health status, and genetics – that may vary from one person to another.
1) Mood
The link between NGF and mood disorders is still unclear.
In one small study, Blood levels of NGF were lower in those with Major Depressive Disorder compared to controls. Larger human studies are needed [9].
In rats, Exercise increased NGF (and BDNF & synapsin I), which was suggested to have improved the survival of neurons in the hippocampus and mood by increasing the serotonin-producing cells in the brain stem. This hasn’t been confirmed in humans [10].
Chrysin is a flavonoid found in honey and some plants. Some scientists think that the chrysin may improve mood in lab animals by raising NGF, but this hasn’t been proven [11].
2) Myelin & Multiple Sclerosis
There’s no evidence about the effects of NGF on myelin and multiple sclerosis in humans.
In an animal model of human brain demyelinating diseases (e.g. Multiple Sclerosis), NGF delayed onset, lowered inflammation, and lessened tissue injury [12, 13].
- Scientists are investigating whether NGF can:
Promote the growth and repair of myelin damage [14]. - Control some of the main structural proteins of the myelin sheath [14].
- Induce the production of BDNF, which is also thought to be important for the myelination of nerves [14].
- Play a role in brain disorders, including Multiple Sclerosis, Alzheimer’s disease, and Parkinson’s disease [15].
None of these effects have been proven. We can’t apply the existing animal data to humans.
3) Alzheimer’s Disease
According to one theory, substances that raise acetylcholine may be beneficial in Alzheimer‘s disease. Recent animal studies proposed that NGF might protect acetylcholine activated neurons, but its effectiveness and safety in Alzheimer’s patients has never been properly investigated [16].
In a study of 10 Alzheimer’s patients receiving NGF gene transfer therapy, the authors observed degenerating neurons sprouting from their axons, tissue growth, and improvement of function. Larger clinical trials are needed [17].
Some researchers hold that the ability of the brain to convert proNGF to mature NGF is faulty in both Alzheimer’s disease and in Down Syndrome, resulting in neurons that are dysfunctional. Amyloid-β plaque formation and brain inflammation are among the possible causes. However, the exact cause of Alzheimer’s is still unknown and likely involves many complex factors [18].
4) Schizophrenia
The impact of NGF on schizophrenia seems contradictory.
On the one hand, studies suggest that certain genetic variations in the NGF and NGF receptor are associated with decreased blood levels of these proteins and an increased risk of schizophrenia [19].
On the other hand, small human studies found higher NGF and BDNF levels in schizophrenia patients. The authors hypothesize that neurotrophins do not always support health – as is often popularly thought – but that they may worsen mental health in certain cases [6].
Thus, the impact of NGF on schizophrenia remains an active and poorly-understood area of research.
5) Heart Health
We don’t know how NGF impacts heart health in humans since all the available data comes from experiments on lab animals.
In a mouse model of injury to the artery, NGF seemed to have regenerated nerves around the blood vessels and subsequently helped form new blood vessels, supporting their development and stabilization [20].
In another animal study, NGF was suggested to help repair the heart after a heart attack [21].
These findings can’t be extrapolated to humans.
6) Diabetes
One hypothesis states that NGF may be important for pancreatic health. Scientists are investigating whether taking NGF away kills pancreatic beta cells, which produce insulin [22].
In small human studies, low blood levels of NGF have been associated with diabetic neuropathy. Larger, better-designed human studies are needed [23].
7) Fertility
Scientists suspect that NGF might be involved in reproductive system health. It has been referred to as Ovulation-inducing factor (OIF) in some studies [24].
Recent studies suggest that it induces ovulation (the release of the egg from ovaries) in some mammals, which may theoretically help with fertility when ovulation is an issue. However, it’s too early to draw any conclusions. Its impact on reproductive health in women hasn’t been tested yet [24].
Researchers are looking to understand if low levels of NGF (and BDNF) in the follicular fluid of the ovary may lessen the ovary’s ability to release egg cells. Some have suggested an association with endometriosis, but this hasn’t been confirmed [25].
Additionally, NGF is thought to be abundant in semen, but its role there is unknown. According to some theories, NGF might increase the sperms’ survival. It’s being researched in the cryopreservation process of human semen [26].
8) Inflammation, Pain, and Injury
It’s assumed that NGF can contribute to pain, though more human data are needed.
Scientists are investigating whether high levels of NGF affect chronic inflammation in lung cells [27].
Human findings have been mixed. Limited studies suggest that NGF may be higher in patients with chronic pain (interstitial cystitis/painful bladder syndrome, chronic prostatitis/chronic pelvic pain syndrome, osteoarthritis, diabetic peripheral neuropathy, and psoriasis), but that wasn’t so in all cases [28].
One hypothesis states that increased NGF might be part of the inflammatory response to brain injury [29, 30].
NGF might activate mast cells, which causes the release of histamine. BDNF and other neurotrophins, however, do not seem to activate mast cells [31].
Research suggests that NGF may play a role in regulating the interactions of the nervous system, hormonal system, and immune system, keeping it in balance. A number of autoimmune conditions seem to have high NGF as well as more mast cells, but larger studies are needed to confirm this link [5].
Recent studies have claimed that NGF is one mechanism by which stress increases inflammation and autoimmunity (neuroimmune interactions). Also, a drug that inhibits NGF is used for arthritic pain [5, 32].
9) Cancer Research
Scientists are exploring whether NGF (as well as BDNF) stimulate the spread and survival of tumor cells and promotes new blood vessel production in tumors [33].
Its potentially protective effects are also being investigated in cancer cells in hypothalamic or pituitary tumors and small cell lung cancer (SCLC) [34].
Cell-based research doesn’t tell us anything about NGF’s effects in living beings. Animal and human studies are needed to understand if NGF affects cancer risk and progression.
Factors that May Increase Nerve Growth Factor (NGF)
When to See a Doctor
If your goal is to increase NGF to improve your mood-related issues – including those of depression or anxiety – it’s important to talk to your doctor, especially your mood is significantly impacting your daily life.
Major mood changes, such as excessive sadness, persistent low mood, euphoria, or anxiety, are all reasons to see a doctor.
Your doctor should diagnose and treat the condition causing your symptoms.
Remember that the existing evidence does not suggest that low brain NGF causes mood disorders
Additionally, changes in brain chemistry are not something that people can change on their own with the approaches listed below. Instead, the factors listed here are meant to reduce daily stress and support overall mental health and well-being.
Therefore, you may try the additional strategies listed below if you and your doctor determine that they could be appropriate. None of these strategies should ever be done in place of what your doctor recommends or prescribes.
Additional Precautions
We’re providing a summary of the existing research below, which should guide further investigational efforts.
The studies listed in this section were mostly done in animals and should not be interpreted as supportive of any health benefit in humans.
Thus, please read through the factors below having all the limitations, caveats, and precautions mentioned above in mind.
Lifestyle
- Social enrichment early in life – Mice reared in a more social environment had higher NGF in selected brain areas (hippocampus and hypothalamus) as adults [35].
- Yoga (even a single 20-minute session) [36, 1]
- Stress reduction – Chronic mild stress decreased the concentration of NGF in the rat hypothalamus [37, 11].
- Exercise: Low-Intensity Resistance Training [38], Treadmill exercise [39, 10], Professional sports [40].
- Falling in love [41]
Supplements
Supplements have not been approved by the FDA for medical use and generally lack solid clinical research. Regulations set manufacturing standards for them but don’t guarantee that they’re safe or effective.
Additionally, supplement-drug interactions can be dangerous and, in rare cases, even life-threatening. That’s why it’s so important to consult your healthcare provider before supplementing and let them know about all drugs and supplements you are using or considering.
Hypothesized to Increase NGF
Proposed mechanisms are stated next to the substance.
These mechanisms are all hypothetical and unproven.
- Butyrate [42]
- PQQ – an antioxidant that is also being researched for stimulating NGF and promoting peripheral nerve regeneration [43].
- ALCAR – claimed to increase levels of neurotrophins such as NGF [44, 45] and affect nerve regeneration in rats.
- Rosemary (Carnosic acid) – hypothesized to induce NGF production [46].
- Quercetin – said to promote nerve growth, and has shown the ability to regenerate peripheral nerves [47, 48].
- Ginkgo Biloba (Has Quercetin) [49]
- Lion’s Mane (Hericium erinaceus) – An edible mushroom that might boost NGF in animals [50].
- Zinc – Zinc may increase NGF in animals; however, memory was improved only when Vitamin A was sufficient [51]. Zinc may also bind to NGF, blocking its effect, but is thought to be lessened under a more acidic pH in test tubes [52].
- Vitamin D3 – The active form of vitamin D is being researched for impacting the NGF concentration in brain cells, alone or with Forskolin [53, 54].
- Melatonin – injections increased NGF in the submandibular gland of mice at a specific dose that can’t be translated to humans [55].
- DHEA – Might induce overproduction of NGF cortical neurons [56].
- Astragalus – The extract may act as a nerve-growth promoting factor [57].
- Huperzine A – An alkaloid from herbs that seems to boost NGF in animals [58].
- Bupleurum (Chinese herb Radix Bupleuri) – Raises blood levels of NGF in animals [59].
- Chrysin – A flavonoid found in honey and some plants, it increases NGF [11].
- Royal jelly – Topically, royal jelly increases NGF in animals [60, 61].
- Rehmannia – Improves learning and memory in rats, possibly due to increased NGF in the hippocampus [62].
- Polygala tenuifolia – The root extract (used in Chinese Medicine) increased NGF in the lab [63].
Hypothesized to Support NGF Activity
- Green Tea/EGCG – Green tea polyphenols increase NGF-induced nerve growth in animals. EGCG is hypothesized to enhance NGF-induced neuronal growth [64, 65].
- Milk Thistle [66]
- DHA (NGF induced neuronal growth) [67, 68].
- Vitamin A (via increased NGF receptors and sensitizing cells to the effects of NGF) [69]
- Phosphatidylserine – thought to protect receptors. PS helps older rats retain more quality neurons and a higher density of NGF receptors [70].
- Gotu Kola (Centella asiatica) – (neurite outgrowth in the presence of NGF) [71]
- Alpha-GPC (choline alfoscerate) – May increase the expression of NGF receptors in the brain [72].
- Uridine + Choline + DHA – Feeding omega-3s (DHA or EPA) to gerbils eating a choline-rich diet improved the nerve membranes, especially when also given with a dietary source of uridine [73]. This combination seemed to improve performance. Scientists are investigating whether [74, 75] uridine converts to a form of choline called GDP-choline when it enters the brain [76]. Uridine Monophosphate (rich in foods such as organ meats, brewer’s yeast, tomatoes, and broccoli) may release uridine in the gut.
- Forskolin [77]
- Genistein [78]
- Nardosinone (from Chinese spikenard) [79, 80]
- 4-O-methylhonokiol – A compound from Magnolia officinalis [81]
Evidence from human studies is lacking.
Hormones and Drug Pathways (Experimental)
Have the following in mind first:
- Hormones (like progesterone and estrogen) and other medications should only be used with a doctor’s prescription.
- These hormonal and drug-related factors are theoretical. They aren’t backed up by solid science. We bring them up for informational purposes.
Researchers suggest that the following hormones may be implicated in NGF signaling:
- Estrogen
- Progesterone
Human data are lacking.
Removal of ovaries (which produce Estrogen & Progesterone) caused a significant decrease of NGF in the uterus [82].
When mice with their ovaries removed were treated with estrogen and/or progesterone, NGF protein levels restored to normal [82].
Removing the ovaries did not affect the NGF levels in the salivary glands or the heart [82].
Some scientists hypothesize that fluctuations in the expression of NGF, in conjunction with other factors, may help to explain gender differences in pain sensation and inflammation. This hasn’t been proven [82].
Additionally, scientists found links between the following drugs and higher NGF levels in animals:
- Idebenone [83, 84] – Thought to stimulate NGF, antioxidant properties have been disputed [83].
- Selegiline (drug) – A metabolite of Selegiline, desmethylselegiline, theorized to elevate NGF, BDNF, and GDNF [85].
- 2-deoxy-D-glucose (2-DG) – A compound suspected to produce ketones. 2-DG significantly increased expression of NGF in mice [86].
- Prescription lithium – increased NGF in specific parts of the brain: frontal cortex, amygdala, hippocampus, and limbic forebrain in adult rats [87].
- NGF eye drops (highly controversial and unproven) [88].
Nicotine is a highly addictive substance that is being researched for affecting NGF in cultured spinal cord neurons. Its risks far outweigh any potential benefits, with the exception of smoking cessation programs [89].
Additionally, Noopept is a potentially dangerous “smart drug” that has been researched for impacting the expression of NGF in rat hippocampus. Noopept is classified as an unapproved new drug by the FDA and its use carries a high potential for harm [90].
NGF & Genetics
rs6330
This SNP changes an amino acid in the NGF gene and may impact its function (G=Ala, A=Val).
The A-allele has been associated with anxiety and low vagal activity in limited studies [91].
- In females, GG had higher levels of anxiety than AG or AA [92].
- In males, GG had lower levels of anxiety than AG or AA [92].
Vagal activity impacts heart rate variability scores:
- In men, GG had a higher heart rate variability (high-frequency power and RMSSD) [91].
- In women, GG had a non-significantly lower heart rate variability [91].
Nerve growth factor (NGF) is hypothesized to play a role in the functioning of the basal forebrain cholinergic neurons, which are involved in attentional systems, and are impaired in Alzheimer’s Disease.
- The G allele was significantly more common in people with ADHD (P=.05) [93].
- The “A” allele was associated with Alzheimer’s [94].
More research is needed.
rs2072446
The T allele was associated with schizophrenia and decreased blood levels of these Nerve Growth Factor. Other studies suggest the opposite. No clear link between NGF and schizophrenia can be established [19].
Although C is the common allele, it has been associated with the risk of Alzheimer’s in people with a family history in extremely limited studies [95].
rs4332358
This SNP was associated with affective disorders such as depression or bipolar in women (doesn’t specify allele) in a single study. This hasn’t been replicated [96].
rs734194
G or the less common allele might be protective against developing schizophrenia [19].
