KĀRMUKATA OF ĀBHYANTARA AND BĀHYA SNEHA

गुरुगुण

It increases the body dimensions including the tissues.

शीतगुण

It makes the body more intact. It create satiety and by which it prevents the occurrence of snehapāna complications such as मूर्च्छा, sweda and dāha

सरगुण

It is spreading in nature. it is the main गुण which makes the snehana to spread all over the body. प्ररेण: वातानुलोमन: qualities are due to saraguṇa hence it helps the doṣas to move to koṣṭha .

स्निग्धगुण

Snigdha guṇa brings softness to the tissue and cause दोषोत्क्लेशन

It brings softness to the body and स्रोमृदुगुण

तस् brings looseness and laxity in doṣasaṅghāta.

सूक्ष्मगुण

Because of सूक्ष्मगुण sneha enters to the minute channels of the body. sūkṣma has the srotoviśodhana properties. Which brings the vitiated doṣas to the koṣṭhas. Some आचार्य says it has the quality of dilating of the channels which augment the movement of sneha dravyas freely into the minute channels.

द्रवगुण

It helps the snehadravya to diffuse all over the body . It also helps in the doṣavilayana process. It also acts like a dissolving media to the doṣas by āloḍanasandhāna kāraka properties.

स्नेहोऽनिलंहन्तिमृदुकरोतिदेहंमलानांविनिहन्तिसङ्गम्।

चक्रपाणि says these are the functions of शोधनाङ्गस्नेह

 Sneha is having the opposite quality of vāta hence subside the vāta doṣas.it altars गति of vāta which brings the शाखागतदोषा  to कोष्ठ

Sneha by virtue of its snigdha or mṛdu qualities brings softness in doṣas, srotas and deha.

It is very important to bring the doṣas to koṣṭha in उत्क्लेश stage. This mṛdukarana effect is seen by गात्रमार्दवं.

Mala saṅga occurs due to रूक्षण. snehana overcomes this रूक्षण quality due its snigdha and vishyandana properties and by which saṅga is released.

Along with the above actions in the body it acts as a solvent, increasing the आप्यांश of the body.

The disease is produced due to the sthānasaṃśraya of vitiated doṣas through srotasas. Snehana administered internally reaches each and every srotas of the body and acts as a solvent to remove the obstruction by dissolving the morbid doṣas in it. This results in the removal of srotāvarodha which is one of the important steps in samprāpti vighatana.

Snehapāna as a poorva as well as pradhāna karma is an important treatment procedure that has multiple actions in our body.

While consuming acchapāna properly leads to samyak snigdha lakṣaṇas. which depends upon the koṣṭha and agni of a rogi.

Among the samyak snigdha lakṣaṇas, vāta anulomana -proper downward movement of the abnormal vāta and enhancing the normal functions of organs of the abdomen is prime important. The snigdha guṇa of snehapāna is the main cause of this.

Deeptāgni and Koṣṭha mārdava are due to the stimulation of Pācaka Pitta, Kledaka kapha, and samāna vāta. During the process of snehapāna the stomach acids and the digestive enzymes of the stomach are stimulated. It is due to the prabhāva of ghṛta.

The ghṛta induces the production and secretion of several digestive juices or enzymes necessary for excess lipid molecules to get digested thereby eliminating unwanted molecules away from the body. The term also can be used to indicate the Cellular respiration.

Sneha udvega happens after the vipāka of the snehana substance contains the essence of sneha in it.

snigdha or mṛdudeha – to make each and every cell smooth or unctuous. The cell membrane of all animals contains fatty acids. In high temperature, their bondings can rotate causing chain shortening and make the membrane thinner enabling a rapid exchange of substances between the cells. In Snehapāna, the whole qualities of ghṛta will enter into each cell due to samāna guṇa (equal qualities) of ghṛta and Cell membrane, making the body soft, smooth and unctuous to touch.

Asaṃhata mala or vinihanti malasaṅgam (loose stool) – Due to its snigdha and sara guṇa, snehapāna helps for the easy bowel movement (snigdha saṅgata varcas).

Snehana lubricates the Purīṣavaha srotas also because of which gāḍha varcas are corrected and the lipid molecules entering the intestinal tissues through bile, as well as through diffusion, make them too unctuous and smooth. There will be production of more water molecules within the cells along with other byproducts during the final stage of Lipid metabolism. Such factors might contribute to the Laxative properties during snehapāna as well as found as a major samyak snigdha lakṣaṇa.

The Drava quality of snehana substance acts as a solvent for many substances within the body. Because it’s a solvent the snehana substance can reach sūkṣma srotas and provide nutrients to every cell of the body. Also this quality of sneha dravya dissolves toxins or metabolic waste products and carries them to the Maha srotas from there it can be expelled easily. Because of these phenomena sroto rodha is prevented by the intake of acchapāna.

The cell membrane of humans is made of the components of Omega -3 and Omega-6 unsaturated Fatty acids, which serve as precursors to bioactive lipid mediators and provide a source of energy.

In Snehapāna or during the period of consumption of medicated ghee, the whole qualities of Ghṛta including the qualities of medicines used in Ghṛta, diffuses into each cell of the body. In turn toxins from cells diffuse back into the Ghṛta medium through active and passive transportation and reach the circulation, ready for expulsion.

In high temperatures, the bandings of Fatty acids can rotate causing chain shortening and make the Cell membrane thinner, so that it enables a rapid exchange of substances between the cells. There will be an increase in Basal metabolic rate during Snehapāna. This aids the exchange processes between the cells as well as between the cells and Ghṛta.

The Sweda karma (sweating procedure) after Snehana procedure, also progresses the exchange processes of substances between the cells. So that more unwanted materials will be moved towards the nearest route, Koṣṭha (GIT) for expulsion, while those accumulated under the skin will be expelled through the minute sweat pores in the skin.

Each and every part of our body is made of various types and compositions of Sneha. Some Unsaturated Fatty acids, a Phospholipid layer Glyco-protien layer, Cholesterol, Carbohydrates and Proteins together constitute the structure of a Cell.

Cholesterol is considered as the precursor of Steroid hormones and Bile acids. They are even necessary for the development of Myelin sheath. Forms the main component of adipose tissue, essential for repairing damaged cells, for Vitamin D synthesis and so on.

Here, Ghee or Ghṛta contain 100% Sneha substances or substances that provide unctuousness to the body. So, if we administer Ghṛta, it will be easy to get absorbed into the cells due to their similarities. Before absorption, it should be broken down into simple substances with the help of enzymes. Whenever a fatty rich food enters the body, Salivary Amylase, Gastrīc Lipase, Lingual lipase, Bile, Pancreatic lipases will act on it and break down into Fattyacids and Glycerol.

Bile salts have detergent action which promote Emulsification. It also has detoxicative functions. Majority of Cholesterol breaks down in the body due to the action of Bile acids.

Nearly 500mg of Cholesterol are utilised for further synthesis of bile acids and excess get eliminated through bile into the Intestine every day, particularly in situations of excess Cholesterol ingestion.

About 95% of Bile acids are absorbed back into blood within the Ileum. Only a small quantity gets lost from the body. In the case of Snehapāna, the same process might be happening. Along with Bile, Pancreatic lipase also converts most of the Triacylglycerol into Monoacylglycerol and Free Fatty acids.

The fatty acids are transported by Plasma albumin and diffuse across the cell membrane, using a protein transporter and form Acyl-CoA in the cytosol. Acyl-CoA molecules cross the inner membrane of Mitochondria. Within the Mitochondrial matrix, β- oxidation takes place. Acetyl-CoA, Water, 5 ATP molecules are the products of each event of Oxidation. Two important enzymes involved in Fatty Acid metabolism are delta-6 denaturise and delta-5 desaturase.

The bile which is normally produced during the period of Snehapāna, has more chance to be excreted out through faeces. This bile carries and eliminates some amount of unwanted Cholesterol along with it.

Bile is one of the major excretory routes for potentially harmful exogenous lipophilic substances, endogenous substrates like Bilirubin, bile salts and for those substances not secreted or filtered properly by the kidney.

Bile also excretes some metals like Copper, Zn, Hg, Pb and so on. The final product Acetyl-CoA molecules involved in many Biochemical reactions in the body such as Cellular respiration and enter the Citric acid Cycle in Mitochondria, react with Oxalic – acetate to form Citrate, which is an excellent Chelating agent.

Two acetyl-CoA molecules condense to form Acetoacetyl-CoA, which give rise to Acetone. Such Ketone bodies released from Liver cells, finally enter the circulations, can cross Blood-Brain barrier, give fuel for CNS, act as a substitute for Glucose. Some Acetyl-CoA molecules act as an important content for the synthesis of a neurotransmitter – Acetylcholine. Acetyl CoA plays a major role in melatonin synthesis – a hormone produced by Pineal gland that regulates sleep and wakefulness. The Acetylation process affects Cell growth and mitosis.

The various functions of Acetyl-CoA show how Samyak snigdha lakṣaṇa happen. The word Vātanulomyata not only means making the movement of Vāta in the right directions, but it also emphasizes all biological reactions, transportations and movements of GIT. Ghṛtapāna or Snehapāna thus helps to regulate all these functions in a smooth, steady way.

Sneha Pāna  And Ketosis

Energy production

After we eat, the carbohydrates are converted into glucose and insulin helps glucose from the bloodstream to get into cells(glycolysis). In the cell, the glucose is converted into pyruvate and the pyruvate is converted into Acetyl-CoA molecule and sent into the citric acid cycle to generate energy (ATP).

Note -Even during glycolysis ATP and NADH is formed. (relatively less)

Our brain cells work hard to understand what is happening around us. The brain cells receive information from various parts of the body and process it in a series of signals and then send more information back to the body. Enormous amount of energy is required for this process. That energy is nothing but adenosine triphosphate (ATP) which we get from our food. Each and every day, cells of the body need thousands of ATP molecules for their proper function. This process is called cellular respiration which makes the energy we need. Glucose and oxygen are the backbones of cellular respiration and the waste product of cellular respiration is carbon dioxide.

Nadh (Nicotinamide Adenine Dinucleotide) & Cellular respiration

NADH is a crucial co-enzyme in making ATP.NADH exists in two forms inside the cell, NAD+ AND NADH. Among these two forms NAD+ is available in the oxidized form. The oxidized molecule (NAD+) can always accept electrons (negatively charged particles). Since NAD+ is negatively charged, it picks up hydrogen atoms from the surrounding environment which is positively charged, and becomes NADH.

This newly formed NADH acts as a carrier of electrons during cellular respiration. At various chemical reactions, the NAD+ picks up an electron from glucose and becomes NADH. The NADH along with another molecule flavin adenine dinucleotide (FADH2) will ultimately transport the electrons to mitochondria and the proteins found in mitochondria convert this electron carried by NADH into ATP.

Ketogenesis

Safely we can say to complete the śodhana process,  we may need 11-21 days (deepāna, pachana, snehana, swedana, śodhana and peyadi). During this period the intake of carbs are drastically reduced and the fat intake goes up so the ketogenesis sets in the body and which in turn produce the ketone bodies. So we can conclude that the entire śodhana process which includes snehapāna turns the body into ketosis mode. The following paragraphs will explain how ketosis is a boon to humanity.

Physiology of ketosis

Ketogenesis is a metabolic pathway that produces ketone bodies, which provides an alternative form of energy for the body. Ketogenesis occurs in day to day life. For example, strenuous exercise, fasting.

The excessive carbohydrate we eat is converted into fat cells by the liver and if the remaining carbs are not utilized, the muscles store these excessive carbs as glycogen.

Normally to create energy either stored carbohydrate or non-carbohydrate substances are utilized and through the process of glycogenolysis, the energy is produced. This involves the breakdown of glycogen stored in muscle and liver. Gluconeogenesis, the production of glucose from noncarbohydrate sources such as lactate, is often utilized as well.

When enough glucose is not available to generate Acetyl-CoA from pyruvate, then Acetyl-CoA is generated from the oxidation of fatty acids and from that ATP is generated to fulfill the energy requirement. The availability of less glucose also builds up Acetyl-CoA in liver cells which in turn induces ketogenesis.

Most organs and tissues can use ketone bodies as an alternative source of energy when it is not available through carbs. The human brain uses ketone bodies as a major source of energy during periods where glucose is not readily available. The heart typically uses fatty acids as its source of energy, but it can also use ketones for its normal function. The liver, although being the primary site that produces ketone bodies, cannot use ketone bodies as a energy source because it lacks the necessary enzyme beta ketoacyl-CoA transferase.

Benefits of ketogenesis

In humans, ketone bodies are the only additional source of brain energy after glucose. Thus, the use of ketone bodies by the brain could be a significant evolutionary development that occurs in parallel with brain development in humans.

A ketogenic diet is clinically proven in controlling epilepsy seizures. The Effect of the ketogenic diet on epilepsy may be due to the increased availability of beta-hydroxybutyrate, a ketone body transported through the blood-brain barrier. In support of this claim, it was found that a ketogenic diet was the treatment of choice for glucose transporter protein syndrome and pyruvate dehydrogenase deficiency, which are both associated with cerebral energy failure and seizures.

Beneficial changes in the brain energy profile have been observed in subjects who are on a ketogenic diet. This is an important observation because cerebral hypometabolism is a characteristic feature of those who suffer from depression, mania or bipolar illness.

In diseases such as alzimers, Parkinson’s, dementia etc the neurotransmitters are not able to transport the signals processed by the brain to the target organ. It’s found that a low carb diet improves signal transduction in neurons by inducing changes in the basal status of protein phosphorylation. This phenomenon greatly increases the quality of life in those people who suffer from the above diseases.

NOTE – This could be the reason why in the diseases like अपस्मार (convulsions) उन्माद (schizophrenia) and various वातव्याधि’s where commonly cell degeneration is noted, more घृतप्रयोगा is advised by our आचार्य.

It is assumed that the consumption of a high-fat diet causes obesity because fat has a higher caloric density than carbohydrate. On the contrary, recent studies have proved that a high-fat diet regime can help in reducing weight.

 It’s a known fact that a diet with a high glycemic load is associated with the development of cardiovascular diseases, type II diabetes and certain forms of cancer. So the ketogenic diet which induces ketosis in the body is highly helpful in controlling these diseases.

 Sugar consumption is positively associated with cancer in humans and test animals. This observation is quite logical because tumours are known to be enormous sugar absorbers. It’s found that the risk of cancer decreases with an increase in total fat intake from various studies. But further concrete evidence is required to establish this theory.

गुडानूपामीषक्षीरतिलमाषसुरा दधि | कुष्ट शोफप्रमेहेषु न प्रकल्पयेत्|

त्रिफलापिप्पलीपथ्यागुग्ग्लुवादिविपाचितान् ||.

Either ghee or oil, processed with lekhana dravya like triphala, pippali, pathya, guggulu are highly beneficial in prameha, kuṣṭa sthoulya etc diseases.

 It is very clear that these diseases are kleda Pradhāna in nature. Dravya like Guḍa, sharkara, anoopa māmsa, milk etc must not be used in these diseases either alone or with snehapāna because these dravya”s increase the kledatwam inside the body and this increased kledatwam is responsible for the chronicity of these diseases. Snehapāna with lekhana dravyā’s help to induce ketosis in these diseases which in turn helps to control them.

Note: I have compiled this from various sources available in google with my own inputs. Thanks to various authors who have given their views on various websites.

Some thoughts:

Snehapāna involves a large quantity of fat intake. Body cannot take excessive fat suddenly and may lead to complications like fat embolism. Intake of saturated fat suddenly in large quantities can cause a rise in LDL cholesterol in the blood and may increase inflammation in cells. That’s the reason why large dose of oily substances are not given suddenly in a day where as it is given in small doses for 3 to 7 days.

 Even Ācāryas says that using too much quantity of fat suddenly can kill the person. अञ्जातकोषटे: बहुकुर्यात्प्राणसंशयं।. This is the main reason why it is advised to take snehapāna in ārohaṇa kramam which involves gradual increase of fat every day.

The ārohaṇa kramam is also advised for the acceptance of sudden metabolic changes which occurs in the body during shodanāṅga snehapāna process. Aārohaṇa snehapāna  also helps to induce a smooth ketogenesis process.

While it’s clear that saturated fats can increase low-density lipoprotein (LDL) and certain other risk factors, such as inflammation, it’s unclear whether saturated fats increase the risk of heart disease. For example, a 2014 review of 32 studies that included 27 randomized control trials involving over 650, 000 people found no association between saturated fat intake and heart disease.

In India, ghee used to be the preferred edible fat. Lately, it has come under a cloud—its high content of saturated fatty acids and cholesterol is believed to be responsible for the increased prevalence of coronary artery disease in Indians. The doubt about ghee exists because people confuse ghee with any other saturated fat but the truth is Ghee has a very unique carbon atom structure that is much smaller than the one which is found in commonly feared saturated fat. This unique carbon atom chain is what gives ghee all its therapeutic and almost magical properties says Diwekar (a Mumbai-based dietitian and author of books such as Don’t Lose Your Mind, Lose Your Weight and Women And the Weight Loss Tamāṣa).

A 2011 study by scientists from the National Dairy Research Institute in Haryana, published in The Indian Journal of Medical Research, states that ghee from cow’s milk could protect us from cancer as it “enhances the availability of enzymes responsible for detoxification of cancer-causing substances.

Ghee serves as an antioxidant and is good for the immune system. Besides, it has a high concentration of butyric acids and fatty acids that contain antiviral properties.

 Sesame oil is rich in polyunsaturated and monounsaturated fats, and low in saturated fats, ” says Edwina Clark, RD, and head of nutrition and wellness at “Monounsaturated and polyunsaturated fats are ‘heart healthy’ and help keep cholesterol under control, ” says Clark. We all know monounsaturated and polyunsaturated fats are always beneficial to health.

So we can safely assume that snehapāna which commonly involves, intake of large quantities of ghee, could act as immune booster, antioxidant and anti-cancer and also snehapāna may increase LDL cholesterol in the blood (In some patients) but it will not be the cause for inducing heart diseases.

It is also very clear that the process of snehapāna induces ketosis and ketosis is very beneficial in a number of chronic diseases. Though globally it is considered taking ghee or sesame oil is not good for health, contrary to this belief the above evidence proves that they both are very good and helps in healing many diseases.

I do feel that by processing with the herbs both ghee and sesame oil  transform themselves from saturated fats to unsaturated fats. Since we all know

संस्कारोगुणान्तराधानं उच्यते – Processing changes the internal qualities of the food or herbs.

Autophagy & Lipophagy & Snehapāna

Definition:

Auto means-self

phagy means eat- literally the cell eats its own content.

 If the cell feels that its own cytoplasmic organelle are problematic then that cell will get rid of those problematic organelle by fusing with lysosome.

 One of the two major protein degradation systems is all forms of life from Fungi (protozoa, animals etc also) to plants. The second system is the proteasomal degradation pathway.

 Bulk degradation of cellular components happens through autophagy. The autophagosome which is formed through autophagy degrades substrates like proteins, lipid droplets or organelles within the lysosome. Autophagy is responsible for cellular waste clearance and also recycles nutrient substances like amino acids. Autophagy is very important for cell homeostasis.

Although it was initially thought that autophagy was a non-selective bulk degradation pathway, it is now widely accepted that there are two types of autophagy, non-selective and selective.

 In response to starvation or nutrient deprivation, non-selective autophagy is activated to provide cells with essential amino acids and nutrients for their survival (physiological autophagy). In contrast, selective autophagy occurs to specifically remove damaged or excessive organelles, Pathogens or protein aggregates even under nutrient-rich conditions (Pathological autophagy).

There are three different mechanisms through which autophagy happens:

1)  Chaperone mediated

2)  Micro autophagy

3)  Macro autophagy

Among these three, Macro autophagy is very important.

Macroautophagy

 Macroautophagy is a genetically programmed, evolutionarily conserved catabolic process that degrades cellular proteins, and damaged or excessive organelles through the formation of a double-membrane structure known as the autophagosome.

 Different types of macro autophagy are named according to what they actually degrade. For e.g,

1. Mitophagy       –   Bulk degradation of mitochondria
2. Reticulophagy       –   Bulk degradation of endoplasmic  reticulum in the lysosome.
3. Nucleophagy       –   Degradation of nucleus in lysosome.
4. Lipophagy             –   Degradation of lipid droplets
5. Xerophagy –   Degradation of foreign microorganism such as bacteria

Other than these there are various autophagia mechanisms. However, these five are very important.

Formation of autophagosome

Autophagosomes are formed from the endoplasmic reticulum wall. The autophagosome is a double membrane structure which engulfs the protein needed to be degraded. For the selective degradation of the malfunctioning proteins, we need to separate them from cytoplasmic proteins. It can be achieved only through autophagosomes.

Mechanism:

From the endoplasmic reticulum, a small waxing crescent moon shaped double membrane is formed which is called pre autophagosome membrane. This process is called the autophagosome initiation. Various proteins like ULK-1, ATG (autophagy-related protein)-101, ATG-13 are necessary for the pre-autophagosome formation. Among these ULK-1 which is activated by protein, kinaze is very important because this is the one that initiates the process of the autophagosome.

The pre-autophagosome membrane is further developed like a first-quarter moon with the help of proteins like VPS-14, VPS-15 AND BECLIN-1 etc.

Among all these proteins BECLIN-1 is very important in this second stage and it is activated by ULK-1 protein through phosphorylation. These proteins act like class-3 PI3 kinase and (phosphoinositol triphosphate) they produce pep-3 (phospho inositol Diphosphate) from pep-2. This increased concentration of pep-3 leads to the recruitment called WIPI proteins for the further development of the autophagosome. Along with WIPPI protein and other proteins like P62, MBRI is also recruited. Both act as a partial selective receptor for the different substrate of cells.

In the third stage, the autophagosome membrane becomes larger (further developed) like a waxing gibbous moon with the help of The very important protein LC3-1, which helps for the maturation of the autophagosome. Some other protein complexes like ATG-5, ATG-12, ATG-16 help to target particular substrates and particular proteins to develop autophagosomes.

LC3-1 comes from pro LC3. PRO LC3 is cleaved by assisting protease ATG-4 into LC3-1. Once this LC3-1 is targeted to the pre autophagosome membrane it actually gets activated by ATG-7 and bound to ATG-3 and then conjugated to PEO. (PHOSPHOETHANOLAMINE) To form LC3-2. As this conversion from LC3-1 to LC-3 occurs the autophagosome membrane continues to elongate and becomes a full-fledged autophagosome vesicle. This is when we call mature autophagosomes.

This mature autophagosome with its contents fuses into the lysosome with the help of SNARE PROTEINS and RAB-7. Once it fuses with the lysosome it becomes AUTOLYSOSOME. The membranes fuse and the autophagosome releases its content into the lysosome and then those substrates degrade in the acidic lysosome by particular proteases like cathepsin bl and another cathepsin.

Since it’s a very complicated process there are methods to categorize each process.

Initiation         –  Membrane formation from the endoplasmic reticulum.

Nucleation     –  Formation of pep 3 through ULK-1 protein.

Elongation     –  when the autophagy membrane becomes larger through the lc3-1 conjugation process.

Maturation     –  Once the membrane closes and becomes a mature autophagosome vesicle.

Fusion             – Final step fusion with lysosome.

Image showing the autophagosome formation

The autophagy happens inside the lysosome. But Why?

Say if autophagy happens in cytoplasm, and not in autophagosome then the proteolytic enzymes which are secreted by the lysosome can degrade even good and necessary proteins which are present in cytoplasm. So the autophagy must happen in autophagosomes only because the idea of autophagy is to degrade the rogue proteins, not the normal functioning protein. So autophagy must happen inside the lysosome.

How does the cell distinguish between good and bad protein?

Proteolytic signals from proteasomes help autophagosomes to identify good and rouge protein. These proteolytic signals are called protein degrading signals (PDS). These signals are found in the surface of the degrading protein. These signals may be simple amino acid modification like glycosylation. This modification tags the protein with autophagosome membrane. Any kind of signal that tells the different cellular machinery to degrade the protein is called DEGRONS.

How to induce autophagy in day-today-life:

1) By inducing lipophagy

Recently, a close relationship between autophagic activity and lipid metabolism has been recognized. Firstly, lipid droplets are sequestered by autophagosomes and eventually broken down by lysosomes through a process termed lipophagy.

  Lipid overload stimulates autophagy.Elevated autophagy plays a crucial role in counteracting lipo toxicity through mitochondrial quality control.Long-term lipid overload and subsequent autophagic activation place a burden on the lysosomal system, resulting in phospholipid accumulation and inadequate acidification,Lysosomal dysfunction, in turn, stagnates autophagic flux, which can lead to vulnerability to I/R injury during lipid overload, also A high-fat diet (HFD) downregulates autophagy by reducing autophagosome/lysosome fusion, as well as by decreasing the number and the acidity of lysosomes.

  The conflicting results may be attributed to differences in cell types, observation period, FFAs concentration and, more likely, difficulty in monitoring autophagic flux in vivo.

2. Intermittent Fasting/Fasting

Since autophagy is closely regulated by nutrient deprivation, one of the best ways to induce autophagy is by intermittent fasting. Intermittent fasting is a time-restrīcted eating plan with a no-eating ‘fasting’ period and an eating ‘feeding’ period. Intermittent decreases insulin levels and increases glucagon levels which encourages an increase in autophagy.

Short-term fasting resulted in a dramatic increase in autophagy in the brain. Neuronal autophagy is incredibly vital in fighting degenerative diseases such as Parkinson’s.

Intermittent fasting increases neuronal autophagy in cortical neurons and Purkinje cells, which are important neurons and nerve cells critical to brain function. Autophagy in the brain occurs through changes in autophagosomes (a fundamental organelle in autophagy), and by decreased TOR activity.

2. Ketogenic Diet

The ketosis diet is a high-fat, low-carb diet that may also be able to induce autophagy.Ketosis requires an intense reduction in calorie intake, which reduces insulin levels and therefore increases glucagon levels, leading to an increase in autophagy. Incorporating more fat and protein in response to the reduction of dietary carbs has led to concerns on the effect of low-carb dieting on lipids; specifically, LDL cholesterol. Recent systematic reviews of low-carb diets on lipids demonstrate a neutral to small increase in LDL but a favorable triglycerides reduction and an increase in HDL cholesterol, particularly those assigned to the very low-carb intervention

A ketogenic diet can reduce the activity of TOR kinase in the hippocampus, an area of the brain. TOR acts as an autophagy blocker, so the ketogenic diet may be able to increase autophagy by decreasing TOR levels.

3. Exercise:

Studies suggest that exercise increases Sirt1 levels, which is closely associated with insulin regulation, and also increases AMPK activation. APK is a protein kinase that increases glucagon levels. Exercise may increase autophagy levels by decreasing insulin levels, and thus growing glucagon to induce autophagy, and also by increasing AMPK activation to increase glucagon levels directly.

Benefits of autophagy:

Autophagy is beneficial in preventing the following conditions.

• while the body can do this clean up alone, and indeed autophagy is active in all cells, there are many benefits to encouraging regular autophagy:
• Regulates cellular mitochondria, which improves energy production in the body.
• Protects the nervous system and the immune system.
• Protects against metabolic stress.
• Encourages growth of new cells, especially those in the brain and heart tissue, enhancing cognitive function and protecting against heart disease.
• Helps improve digestive function by repairing and restoring the gut lining.
• Helps to protect our genes by maintaining the integrity and stability of our DNA.
•  Genetic links have emerged between autophagy defects and cancer, providing increasing support for the concept that autophagy is a bona fide tumor suppressor pathway

Cancer

Autophagy can act as a tumor suppressor, and loss of autophagy promotes tumorigenesis. An essential autophagy gene, Beclin 1, was frequently found deleted in many human cancers such as breast, prostate, and ovarian cancers.

Neurodegenerative diseases

 As discussed above, some familial forms of Parkinson’s disease are provoked by mutations in Pink1 or Parkin, some of which can result in defects in mitophagy. In addition, mitophagy may also play a role in other neurodegenerative diseases including Alzheimer’s disease (AD) and Huntington’s disease (HD).

Innate immunity

Accumulating evidence now supports the idea that autophagy is closely associated with innate immunity. Autophagy plays an important role in defending against invading intra-cellular microbes, including Mycobacterium tuberculosis, Salmonella Listeria, Shigella, HIV-1, and Sindbis viruses.

Tissue injury

It has been well known that the mitochondrion is a central executioner for regulating cell death In response to apoptotic stimuli. It found that Parkin-mediated mitophagy has a protective role against the cell death of cardiomyocytes.

In addition to regulating cell death, mitochondria also play an important role in regulating lipid homeostasis by burning fat through fatty acid β-oxidation. Decreased autophagic activity is found in the livers of obese mice, and genetic deletion of Atg7 or pharmacological inhibition of autophagy is associated with hepatic steatosis.

induction of autophagy leads to reduced alcohol-induced hepatic steatosis. Although autophagy may selectively remove lipid droplets (lipophagy), removal of damaged mitochondria may also contribute to the attenuation of steatosis. Therefore, targeting damaged mitochondria by activating autophagy may be a novel approach for treating damaged mitochondria-mediated tissue injury in the future.

Postponing old age

 Conditions that activate autophagy, such as caloric restrīction, have shown beneficial effects on delaying the ageing-related degeneration process. Stimulation of autophagy has been shown to extend the life span in multiple organisms.

Although the exact mechanisms by which autophagy may delay ageing are not clear, it has been suggested that autophagy may help reduce the production of mitochondria-derived ROS and remove dysfunctional mitochondria that would generate MTDNA mutations during ageing.

Lipophagy as a Subset of Autophagy

Lipid droplets (LDs) are cytosolic organelles that have a specific cellular function. The autophagy pathway is turned on through the process of lipophagy.

Lipid droplets (LDs) are eukaryotic organelles responsible for the storage of lipids in the forms of triacylglycerols (TAGs), cholesteryl esters and retinyl esters surrounded by a phospholipid monolayer.

The surface of the droplets is also coated with proteins, such as the perilipins; these are a family of five proteins that contribute to lipid droplet packing and regulate interactions with other organelles.

Lipid droplets allow for the storage of lipids that can be utilized for energy production as well as the synthesis of membrane components. Such lipid storage protects the cells from exposure to excessive amounts of free fatty acids (FFAs) and sterols that can be damaging to cellular membrane composition. The lipids can be accessed when needed through the process of lipolysis, which involves the breakdown of TAGs and esters by cytosolic lipases, such as Adipose Triglyceride Lipase (ATGL).

 In addition to lipolysis, lipid stores can also be accessed via lipophagy, a specific subset of selective autophagy that targets LDs and catabolizes their components into FFAs and glycerol.

 Lipophagy impacts the cellular energetic balance directly, through lipid breakdown and, indirectly, by regulating food intake. Defective lipophagy has been already linked to important metabolic disorders such as fatty liver, obesity and atherosclerosis, and the age-dependent decrease in autophagy could underline the basis for the metabolic syndrome of ageing

Dual-Effect of Lipids on Autophagy

Numerous studies have confirmed the stimulatory effect of dietary lipids on the autophagic process. Upregulation of autophagy in response to increased FFA has been demonstrated in neurons, muscle, pancreas, mammary epithelial cells, liver-derived cells, and even in colon cancer cells.

 In contrast to this stimulatory effect of a lipid challenge on the autophagic system, an equal number of studies have started to report inhibition of autophagy in response to exposure to high concentrations or a particular type of lipid. For example, unsaturated FFA such as oleic acid has a marked stimulatory effect on autophagy in many cells, at least up to some concentrations. In contrast, saturated FFA such as palmitic acid—may be due in part to its lower incorporation into LD—remains in the cytosol at higher concentrations and suppresses autophagy.

Animals exposed to a high-fat diet for prolonged periods increase the autophagic activity during the first weeks of treatment, which is progressively followed by a gradual decrease in autophagy. This decrease further contributes to the expansion of the LD compartment, eventually leading to hepatotoxicity and steatosis.

 Alterations in the autophagic system and in its ability to mobilize intracellular lipids may underline the basis of important human disorders. The possible links of lipophagic malfunctioning with obesity, atherosclerosis, and the metabolic syndrome of ageing are depicted.

The Significance of Lipophagy and Aging

Experiments have shown that HLH-30/TFEB- mediated autophagy is a critical component of long lived phenotypes and that the induction of lysosomal lipases can have a positive effect on organismal lifespan. LIPL-4, in particular, is a lipase that is necessary for longevity in germline-less worms, and whose overexpression extends lifespan in an autophagy dependent fashion.

Alcoholic Fatty Liver Disease

 Alcoholic fatty liver disease (AFLD) refers to the damage caused to the liver by excessive consumption of alcohol. The symptoms include oxidative stress, lipid droplet accumulation in the cytoplasm of hepatocytes, mitochondrial damage and cell death. In particular, steatosis (excessive LD deposition) is an extremely common symptom of alcohol abuse AFLD is a multifactorial disease that involves interactions between lipid metabolism, the immune system and oxidative stress

It has been found that, upon short-term supplementation, ethanol induces mitophagy and lipophagy in hepatocytes, which likely act as repair mechanisms against damage caused to mitochondria. Ethanol-mediated mitochondrial damage leads to an increase in intracellular ROS, which can induce autophagy through Beclin-1 as a means to combat oxidative damage.

 Nonetheless, chronic alcohol exposure causes impairment of autophagy and lipophagy. This impairment is most likely caused by activation of mTOR signalling and a reduction of lysosomal biogenesis in hepatocytes. Administration of the mTOR inhibitor Torin-1 to these mice restores lysosomal biogenesis and decreases steatosis and liver damage.

Non-alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is an umbrella term used for numerous liver- related conditions characterized by the accumulation of triglycerides in hepatocytes that is caused by an upregulation of free fatty acid levels and lipogenesis.

NAFLD generally involves insulin resistance and the redirection of glucose from glycogen synthesis to lipogenesis. in HepG2 and PLC/PRF/5 cells. This phenotype can be rescued via treatment with the autophagy inducer rapamycin.

 Induction of autophagy by FGF21 supplementation was successful in treating the NAFLD. All in all, the majority of studies indicate that lipophagy counteracts the progression of NAFLD.

Liver Fibrosis

The term liver fibrosis is used to describe the common pathways of chronic or iterative damage that can be afflicted onto the liver by toxic factors, viral infections, autoimmune conditions, or metabolic and aging aspects. Inducing autophagy through Rapamycin slowly helps in reversing the fibrosis through new liver cell formation.

Lipophagy and Cancer

Tumours grow in a unique microenvironment with an insufficient supply of oxygen and nutrients. Survival in such an environment requires metabolic reprogramming. A significant part of this reprogramming involves changes in lipid metabolism, with aggressive tumours exhibiting increased acquisition, production and storage of lipids and lipoproteins. Autophagy has been shown to have both pro-and anti-cancer roles. For instance, it can be anti-oncogenic by inhibiting inflammation or pro-oncogenic by protecting tumour cells from ROS damage due to hypoxic stress and preventing necrotic cell death.

Similarly, lipophagy can also have a dual role in cancer growth. On the one hand, lipophagy contributes to the mobilization of stored lipid content, allowing tumour cells to access a supply of energy that can be critical to their growth. CCĀT enhancer binding protein α (C/EBPα), a protein that is upregulated in hepatocellular carcinoma (HCC) patients, promotes resistance to energy starvation and carcinogenesis through lipophagy. On the other hand, lipophagy has been shown to act against tumorigenesis. Lysosomal acid lipase (LAL), the lipase that facilitates lipophagy, has been found to exhibit tumour suppressor activity, as its deficiency permits cancer growth and metastasis through the mTOR dependent activation of myeloid-derived suppressor cells.

Lipophagy in Obesity

A concrete link between lipophagy and obesity has still to be identified, although there are many indicators for such a relationship. Restitution of autophagy through overexpression of Atg7 can restore insulin levels back to normal and improved glucose tolerance.

Note:

An ideal quantity of lipid stimulates autophagy and autophagy counteracts the lipotoxicity through mitochondrial quality control. more than the required quantity of lipid can reverse the autophagy mechanism and will induce lipid toxicity to cells. Lipid toxicity is highly dangerous and eventually, it kills the cell. The conflicting results may be attributed to differences in cell types, observation period, FFAs concentration and, more likely, difficulty in monitoring autophagic flux in vivo. This could be the reason why snehapāna is advised for a maximum of seven days.

High fat more than the required quantity can down-regulate autophagy by reducing autophagosome lysosome fusion. whereas a low-fat administration less than the requirement of the person may not trigger autophagy this could be the reason why the dose of snehapāna is fixed after studying the requirement of the person by understanding the agni and koṣṭha.

The diet during, after and before snehapāna contains low carbs and high proteins and snehapāna is pure fat administration. This mechanism triggers autophagy lipophagy which acts against disease formation. This mechanism also stimulates the immune system and a properly working immune system is always important for disease prevention. This is the reason why śodhana is advised on different seasons as a preventive measure.

High quantity of fat also stimulates PURKINJE cells through lipophagy which are important for normal brain function.

Administration of snehapāna may reduce the insulin levels and the reduced insulin increases the secretion of glucagon. Increased glucagon levels triggers autophagy. This reduction in insulin and increased glucagon is always beneficial in counteracting obesity, diabetes Mellitus, pcos, and high serum triglycerides levels. Restitution of autophagy through overexpression of Atg7 also can restore insulin levels to normal and improved glucose tolerance.

The studies show that high fat intake always reduces triglycerides levels and only a small increase in LDL or no increase at all. This has been proved from various studies of different Ayurveda universities. A rise in cholesterol during keto or low-carb eating may be related to losing weight. It’s been known for decades that major weight loss can lead to a temporary rise in LDL cholesterol. The process of making ketones requires a compound called acetyl-CoA, which is a precursor to cholesterol. Having more acetyl-CoA in circulation could theoretically increase cholesterol synthesis. Most cholesterol blood tests measure LDL-C, the total amount of cholesterol carried in our LDL particles. However, LDL-P, or the total number of LDL particles in our blood, is an even better marker of cardiovascular risk. Some studies on low-carb diets have shown an increase in LDL-C without a change in LDL-P (or Apo B, which is a proxy for LDL particles). LDL consists of several subclasses of particles with different sizes and densities, including large buoyant (lb) and intermediate and small dense (sd) LDLs.

It has been well documented that sdLDL has a greater atherogenic potential than that of other LDL subfractions and that sdLDL cholesterol (sdLDL-C) proportion is a better marker for prediction of cardiovascular disease than that of total LDL-C. 

Studies show that carbohydrate restrīction (Which happens during snehapāna) can change small LDL particles into larger ones. So during snehapāna the LDL-C may go up but surely LDL-P would go down and which is very best for overall health.

The high fat intake may decrease TOR KINASE. Which is found in HIPPOCAMPUS of the Brain. The increased TOR KINASE always blocks the autophagy formation in chronic diseases. So snehapāna could reduce the TOR KINASE formation in the brain by that the autophagy is induced and in turn autophagy helps to fight the chronicity of the disease.

Snehapāna  could help in the formation of BECLIN-1 protein which is found not active in people who are prone to cancer. Activation of BECLIN-1 protein by snehapāna could possibly prevent cancer formation in those people who don’t have that protein.

Cell death occurs prematurely in old age because of dysfunctional mitochondria. snehapāna might induce autophagy which in turn help in the removal of dysfunctional mitochondria that would generate MUTATIONAL DNA during old age. Postponement of old age and preserving the youth is one of the main functions of snehapāna.

Parkinson’s disease is provoked by mutations in Pink1 or Parkin, some of which can result in defects in mitophagy. Snehapāna  induced autophagy could help in the formation of proper mitochondria. Proper formation of mitochondria in brain cells is very important for the production of dopamine which is impaired in Parkinson’s disease.

Chronic inflammation and oxidative stress are considered two key factors in the development of Alzheimer’s disease, underlying neurotoxic mechanisms leading to neuronal death occurring in the brain areas responsible for memory and cognitive processes. A bulk of studies have shown that the blood-brain barrier is impaired in Alzheimer’s disease resulting in an altered expression of some transporters, including the down-regulation of glucose transporters.

The primary fuel for the brain is glucose that must be taken from the blood and transported across the BBB by the specific glucose transporters (GLUTs) due to the inability of neurons to synthesize or store it. When there is a decreased expression of these transporters, as it has been shown in AD, Ketone Bodies (KBs) become the alternative energy source to glucose for the brain due to their ability to cross the BBB carried by specific transporters that are not down-regulated during AD.

High fat intake could decrease the activation of microglia and its products IL-1beta, IL-6, TNF-alpha, sparing at the same time tyrosine hydroxylase (TH)-positive neurons in substantia nigra, Moreover, the deficit of motor function induced by mPTP could significantly recovered by high fat intake.

 Snehapāna a induced ketone bodies could reduce the oxidative stress and inflammation of the brain cells and favour the tropism of neuronal cells in the course of AD. The beneficial effects of high fat intake for enhancing cellular metabolism and mitochondrial function, inducing a shift in energy metabolism, which is highly beneficial in various neurologic diseases.

If we carefully observe the benefits of snehapāna, it is very good for chronic diseases and those having issues with the immune system. From the above explanation, it is very clear that autophagy is an important process that helps in a number of diseases and helps in preserving the youth. Today, lifestyle diseases are on the rise and the scientific community is still searching for the best possible cure. However, the age-old science of Ayurveda has a perfect answer for those diseases in the name of dinacaryā, ṛtucaryā and sadvṛtta. Following these three regimens helps a person to live long and also prevents numerous diseases. Fats like ghee play a very important role in preventive medicine. The snehapāna induces xenophagy, microphagy, lipophagy and reticulophagy which in turn leads to preventions of various diseases and postpones old age. Snehapāna removes bad proteins, dead cells and bad organisms through lipophagy mechanism, thus preventing premature cell death and which helps to lead a long life.