For everything there is a season. There is a time to feast, a time to go hungry, and a time to consider your options. I propose to start at with an hors d’ouevre, meander through the middle course and finish with a just desert.
Fade up from red to reveal a foetus bathing in amniotic fluid, its umbilical cord disappearing out of frame.
—Narrator: ‘The start of life, or close enough. The child gets its nutrition from the mother. But who does she get it from?’
Cut to shot of hospital lobby with a McDonalds outlet (ie Jackson Memorial Hospital in Miami).
—Narrator: ‘Not such a good start, then. This mother loves junk foods, just as well since it’s all she can afford. Her mother used to cook but this Gen Z mum doesn’t have time for that. She started eating ultra-processed while she was at high school and college and acquired a taste for it. Not surprising. It’s cheap, it’s everywhere and it is near-addictive.’
Cut to a delivery ward. A near-term woman lies on the bed with hospital staff around her.
—Narrator: ‘And it will cast a long shadow over this new life, from childhood to old age and death. Which will likely come sooner than nature intended.’
Curtains are pulled across the lens / wipe to reveal a researcher sitting in front of a computer screen, scrolling through a PubMed page. Or at a lab bench, if that’s your preferred stereotype.
—-Narrator: ‘There is so much evidence now that what the mother – and to a small extent the father – eats, will impact on the child’s health- and life-span. The story starts two decades ago, when Hales and Barker first proposed the thrifty phenotype hypothesis (1-3) …
If a foetus cannot obtain all it needs for healthy growth, the inherent drive for life leads it to alter its metabolism and the structure of many of its organs in order to survive. Most of these changes appear to be permanent, and what allowed short-term survival becomes a long-term handicap. These children will grow old enough to breed, so our selfish genes win out. But there is a heavy cost.
Low birth weight babies which are still underweight at one year have abnormal glucose tolerance, a high risk of type 2 diabetes and the highest mortality rates from ischaemic heart disease (2, 3). These findings have been replicated by many other researchers (ie 4-10).
Pre-clinical studies have shown that foetal dysnutrition creates long-term changes in the structure and functioning of inter alia the pancreas (11-13), muscle (14, 15) and adipose tissue (16). These changes are largely driven by the mother’s glucocorticoid stress hormones (17, 18). They all predispose to insulin resistance, they match the clinical findings almost exactly, and they make sense.
If a foetus is starved of nutrition, it will instruct peripheral tissues via epigenetic mechanisms to turn away glucose (and other nutrients) in order to divert them for structures essential for short-term survival, such as the brain. This lays the foundations for diabetes in later life, and may still not be enough to protect the brain if maternal nutrition is bad enough.
The role of dysnutrition and chronic inflammation during pregnancy in causing spectrum disorders in children was discussed in a previous post, ‘Inflamed in the Membrane’. A recent review shows that maternal stress and nutrient restriction during pregnancy create epigenetic and neuroanatomical changes in the developing brain, which will probably be the single most important factor in determining mental ability (19, 20) and health for the rest of that child’s life (21, 22).
Going back to the problems of insulin resistance, prevention is – as always – better than cure. Too often, sadly, there is no cure. If the low birth-weight baby is over-fed and there is rapid ‘catch up’ weight gain, the risks of diabetes, heart disease and mortality increase further (23-27).
With nutrition, timing is everything; but so is the happy medium, because at the other end of the scale, heavy babies have problems of their own. And their numbers are increasing (28), because overweight mothers tend to have over-weight babies (29).
The data are not entirely consistent but it is likely that over-weight babies will grow up to experience an increased risk of obesity (30), type 2 diabetes (29-32), heart failure (33), osteosarcoma (34) and mortality (35).
Heavy-weight babies are victims of a different kind of malnutrition, where a mother’s diet and/or weight have created long-term or gestational diabetes. Her raised blood sugar levels cross the placenta but her insulin cannot, so the foetus must pump out its own insulin to keep its glucose levels somewhat under control. Insulin is a potent growth factor in foetal life, hence the bigger babies. These will go on to become more obese, more diabetic and more disease-prone adults; and to have, in turn, more heavy babies.
This is exactly the same pattern seen in lab rats fed on junk food diets (ie 36-39). Their overweight and diseased offspring display a distinct preference for the same junk food diet that sickened their mothers (40, 41), become obese (42) and go on to develop the same kind of fatty liver disease (43) that now affects a quarter of the world’s population (44). A diet with an abnormally high glycemic load, insufficient prebiotic fiber and plenty of trans fats (45) will do the trick.
Would-be fathers should cut down on junk foods too.
Paternal pre-conceptual diet is known to affect sperm quality (ie 46), and emerging evidence shows that it plays an epigenetic role in shaping the infant’s long-term health prospects also (ie 47, 48).
Our children have become lab rats in a vicious cycle driven by a food industry which is not only killing us in droves but also condemning future generations to ever-increasing degenerative disease, mental illness, accelerated ageing (49-62) and therefore early death.
Anyone old enough to read this, however, should just say no. At least, intermittently. A multinational research group (mostly LA and Milan but also Turin, Genoa and Palermo, with contributions from Berlin and London), has been examining the health benefits of intermittent fasting – and it looks as if this may be an answer to most of the problems listed above.
Repeated water-only fasting periods of 48 hours exert highly protective effects against diabetes cancer, heart disease and neuro-degenerative disease in pre-clinical models (ie 63-67). 2-day total fasts are too difficult for most humans, however, so the team developed an easier format which they termed the Fasting Mimicking Diet (FMD.
The FMD is a very low calorie / low protein diet that is consumed for cycles of 4 consecutive days once a fortnight, or for five consecutive days once a month.
This dietary approach is enough to trick the body into a fasting state and promote multi-systems regeneration, enhanced cognitive performance and health-span (68). It also promotes bone density and hippocampal regeneration in older animals (68, 69), reduces autoimmunity, restores a healthy microbiome and gastrointestinal system (69, 70) and protects against cancer (68, 71). It seems to be as effective as the long-term calorie restriction practised by obsessives.
If you’re going to try intermittent fasting, timing is critical. A minimum of 18 hours/day, with the clock starting in the late afternoon or early evening is best. Our adipose tissue has its own circadian rhythm, and goes to sleep after dark (72). This is why insulin resistance increases at night, why late-night eating fuels weight gain (73, 74) and why eating within 2 hours of going to bed is an independent risk factor for NAFLD (75). (See posts Night and Day, Foie Gras).
But what, you might ask, about protein?
While high protein diets are well tolerated in children and young adults, low protein diets are probably better for older adults and are generally associated with longer health- and life-span (ie 76, 77).
This might be because older adults are more likely to have impaired liver and/or kidney disease; or to have a cancer in situ which could be driven by high IGF1 into clinical cancer (77).
Reduce protein intakes and you reduce IGF1 (78). However, in the elderly IGF1 levels are already low, which tends to make it difficult to maintain muscle mass. Higher protein intakes may therefore play a role in warding off sarcopenia (77), and in cancer cases are generally recommended to reduce wasting.
If you are of pensionable age, therefore, you should aim to be in the Goldilocks zone. Not too much protein, and not too little either.
If you are going to try a low calorie and low protein diet, the quality and source of the proteins you eat becomes more important. There is epidemiological and other evidence that plant-derived proteins may be healthier in older age than animal-derived proteins (ie 77, 79); but this too is a complex issue.
Some amino acids are more equal than others when it comes to triggering the body’s nutrient-sensing pathways, and some researchers believe that plant proteins may score here due to their generally lower methionine levels (ie 80). I am not so sure; rice is an excellent source of methionine, and the proteins in animal and in combined plant dishes (ie rice and beans) contain very similar arrays of amino acids. I think we have to look not only the source of the protein but also how it is cooked, and the presence or absence of other dietary components.
Meats are more likely than plant foods to be cooked at high temperatures, boosting the production of carcinogens (81); and they do not contain dietary fibre.
Prebiotic fibres are exclusively found in plant foods, and have a large positive impact on health and life expectancy (ie 82). If you are going to opt for a diet that is low in protein and want that protein to be good quality and combined with prebiotics, the pre-transitional rice and peas (Caribbean), rice and beans (South America and Asia) or falafel in pitta (the Middle East) are three delicious ways to go.
If you add the Health Protocol, which will reduce neuro-inflammation and therefore IKKβ/NF-κB/GnRH signalling in the hypothalamus (83, 84), you should slow the biological clock even more.
It is effectively impossible to run the kinds of clinical trials that would be required to provide proof of concept, but perhaps we don’t need to. We could play war games instead.
During WW1, the Danish population was forced to reduce calorie consumption for 2 years, but maintained adequate consumption of whole-grain cereals, vegetables and milk. This happy circumstance led to a 34% reduction in death rates (85). During WW2, Oslo citizens experienced enforced calorie reduction of 20% without malnutrition for 4 years, and mortality fell by a similar amount (85).
Death rates falling during war obviously only applies to non-combatants, and are unlikely to occur in WW3 which, if Joe DiMentia has his wag the dog moment, will place all of us in the front line. Notwithstanding, they provide compelling evidence for the virtues of hara hachi bun me, a Confucian teaching that suggests you should leave the table still hungry, hormetic and therefore autophagic (86).
Next week. Sweetening the pot; the health benefits of rare sugars.
- Hales CN & Barker DJ (2001) The thrifty phenotype hypothesis. Br Med Bull 60, 5–20.
- Barker DJ, Winter PD, Osmond C, Margetts B, Simmonds SJ. (1989) Weight in infancy and death from ischaemic heart disease. Lancet 2, 577–580.
- Hales CN, Barker DJ, Clark PMS, Cox LJ, Fall C, Osmond C, Winter PD. (1991) Fetal and infant growth and impaired glucose tolerance at age 64. BMJ 303, 1019–1022.
- Phipps K, Barker DJ, Hales CN, FallCH, Osmond C, Clark PM. (1993) Fetal growth and impaired glucose tolerance in men and women. Diabetologia 36, 973–974.
- Lithell HO, McKeigue PM, Berglund L. Mohson R, Lithell UB, Leon DA. (1996) Relation of size at birth to non-insulin dependent diabetes and insulin concentrations in men aged 50–60 years. BMJ 312, 406–410.
- Pouslen P, Vaag AA, Kyvik KK, Moller Jensen D, Beck-Nielsen H. (1997) Low birth weight is associated with NIDDM in discordant monozygotic and dizygotic twin pairs. Diabetolgia 40,439–446.
- Pouslen P, Kyvik KO, Vaag A, Beck-Nielsen H. (1999) Heritability of type 2 (non-insulin dependent) diabetes mellitus and abnormal glucose tolerance – a population twin study. Diabetolgia 42, 139–145.
- Bo S, Cavelli-Perin P, Scaglione L, Ciccone G, Pagano G. (2000) Low birthweight and metabolic abnormalities in twins with increased susceptibility of Type 2 diabetes mellitus. Diabet Med 5, 365–370.
- Rønn PF, Jørgensen ME, Smith LS, Bjerregaard P, Dahl-Petersen IK, Larsen CVL, Grarup N, Andersen GS. Associations between birth weight and glucose intolerance in adulthood among Greenlandic Inuit. Diabetes Res Clin Pract. 2019 Apr;150:129-137.
- Yokoyama M, Saito I, Ueno M, Kato H, Yoshida A, Kawamura R, Maruyama K, Takata Y, Osawa H, Tanigawa T, Sugiyama T. Low birthweight is associated with type 2 diabetes mellitus in Japanese adults: The Toon Health Study. J Diabetes Investig. 2020 Nov;11(6):1643-1650
- Dahri S, Snoeck A, Reusens-Billen B et al. (1991) Islet function in offspring of mothers on low protein diet during gestation. Diabetes 40, 115–120.
- Petrik J, Reusens B, Arany E et al. (1999) A low protein diet alters the balance of islet cell replication and apoptosis in the fetal and neonatal rat and is associated with insulin-like growth factor-II. Endocrinology 140, 4861–4873.
- Cherif H, Reusens B, Dahri S et al. (2001) A protein restricted diet during pregnancy alters in-vitro insulin secretion from islets of fetal Wistar rats. J Nutr 131, 1555–1559.
- Ozanne SE, Jensen CB, Tingey KT et al. (2005) Low birth weight is associated with specific changes in muscle insulin signalling protein expression. Diabetologia 48, 547–552.
- Ozanne SE, Olsen GE, Hansen LL et al. (2003) Early growth restriction leads to down regulation of protein kinase C zeta and insulin resistance in skeletal muscle. J Endocrinol 177, 235–242.
- Shepherd PR, Crowther NJ, Desai M et al. (1997) Altered adipocyte properties in the offspring of protein-restricted rats. Br J Nutr 78, 121–129.
- Bertram CE, Hanson MA. Prenatal programming of post-natal endocrine response by glucocorticoid. Reproduction 124: 459–467, 2002.
- Seckl JR. Prenatal glucocorticoids and long-term programming. Eur J Endocrinol 151: U49–U62, 2004
- Hagman E, Danielsson P, Brandt L, Svensson V, Ekbom A, Marcus C. Childhood Obesity, Obesity Treatment Outcome, and Achieved Education: A Prospective Cohort Study. J Adolesc Health. 2017 Oct;61(4):508-513.
- French SA, Wall M, Corbeil T, Sherwood NE, Berge JM, Neumark-Sztainer D. Obesity in Adolescence Predicts Lower Educational Attainment and Income in Adulthood: The Project EAT Longitudinal Study. Obesity (Silver Spring). 2018 Sep;26(9):1467-1473.
- Franke K, Van den Bergh BRH, de Rooij SR, Kroegel N, Nathanielsz PW, Rakers F, Roseboom TJ, Witte OW, Schwab M. Effects of maternal stress and nutrient restriction during gestation on offspring neuroanatomy in humans. Neurosci Biobehav Rev. 2020 Oct;117:5-25.
- Babenko O, Kovalchuk I, Metz GA. Stress-induced perinatal and transgenerational epigenetic programming of brain development and mental health. Neurosci Biobehav Rev. 2015 Jan;48:70-91.
- Crowther NJ, Cameron N, Trusler J, Gray IP. (1998) Association between poor glucose tolerance and rapid postnatal weight gain in seven-year-old children. Diabetologia 41, 1163 – 1167.
- Yajnik C (2000) Interactions of perturbations in intrauterine growth and growth during childhood on the risk of adult-onset disease. Proc Nat Soc 59, 257 – 265.
- Eriksson JG, Forsen T, Tuomilehto J, Winter PD, Osmond C, Barker DJ. (1999) Catchup growth in childhood and death from coronary heart disease: longitudinal study. BMJ 318, 427 – 431.
- Ibanez L, Ong K, Dunger DB, de Zegher F. (2006) Early development of adiposity and insulin resistance after catch-upweight gain in small-for-gestational-age children. J ClinEndocrinol Metab 91, 2153 – 2158.
- Singhal A. Long-Term Adverse Effects of Early Growth Acceleration or Catch-Up Growth. Ann Nutr Metab. 2017;70(3):236-240.
- Ghosh RE, Berild JD, Sterrantino AF, Toledano MB, Hansell AL. Birth weight trends in England and Wales (1986-2012): babies are getting heavier. Arch Dis Child Fetal Neonatal Ed. 2018 May;103(3):F264-F270.
- Hu Z, Tylavsky FA, Han JC, Kocak M, Fowke JH, Davis RL, Lewinn K, Bush NR, Zhao Q. Maternal metabolic factors during pregnancy predict early childhood growth trajectories and obesity risk: the CANDLE Study. Int J Obes (Lond). 2019 Oct;43(10):1914-1922.
- Woo Baidal JA, Locks LM, Cheng ER, Blake-Lamb TL, Perkins ME, Taveras EM. Risk Factors for Childhood Obesity in the First 1,000 Days: A Systematic Review. Am J Prev Med. 2016 Jun;50(6):761-779.
- Knop MR, Geng TT, Gorny AW, Ding R, Li C, Ley SH, Huang T. Birth Weight and Risk of Type 2 Diabetes Mellitus, Cardiovascular Disease, and Hypertension in Adults: A Meta-Analysis of 7 646 267 Participants From 135 Studies. J Am Heart Assoc. 2018 Dec 4;7(23):e008870.
- Vohr BR, Boney CM. Gestational diabetes: the forerunner for the development of maternal and childhood obesity and metabolic syndrome? J Matern Fetal Neonatal Med. 2008 Mar;21(3):149-
- Rashid A, Agarwala A, Novak E, Brown DL. Association of High Birth Weight With Incident Heart Failure in the ARIC Study. J Am Heart Assoc. 2019 May 7;8(9):e011524.
- Chen S, Yang L, Pu F, Lin H, Wang B, Liu J, Shao Z. High Birth Weight Increases the Risk for Bone Tumor: A Systematic Review and Meta-Analysis. Int J Environ Res Public Health. 2015 Sep 9;12(9):11178-95.
- Kristensen P, Keyes KM, Susser E, Corbett K, Mehlum IS, Irgens LM. High birth weight and perinatal mortality among siblings: A register-based study in Norway, 1967-2011. PLoS One. 2017 Feb 28;12(2):e0172891.
- Petry CJ, Ozanne SE, Wang CL, Hales CN. (2000) Effects of early low protein restriction and adult obesity on rat pancreatic hormone content and glucose tolerance. Horm Metab Res 32, 233–239.
- Petry CJ, Dorling MW, Pawlak DB, Ozanne SE, Hales CN. (2001) Diabetes in old male offspring of rat dams fed a reduced protein diet. Int J Exp Diabet Res 2, 139–143.
- Samuelsson AM, Matthews PA, Argenton M et al. (2008) Diet-induced obesity in female mice leads to hyperphagia, adiposity, hypertension and insulin resistance in a novel murine model of developmental programming. Hypertension 51, 383–392.
- Nivoit P, Morens C, Van Assche FA et al. (2009) Established diet-induced obesity in female rats leads to offspring hyperphagia, adiposity and insulin resistance.
Diabetologia 52, 1133–1142.
- Bayol SA, Farrington SJ, Stickland NC (2007) A maternal ‘junk food’ diet in pregnancy and lactation promotes an exacerbated taste for ‘junk food’ and a greater propensity for obesity in rat offspring. Br J Nutr 98, 843–851.
- Portella AK, Kajantie E, Hovi P, Desai M, Ross MG, Goldani MZ, Roseboom TJ, Silveira PP. Effects of in utero conditions on adult feeding preferences. J Dev Orig Health Dis. 2012 Jun;3(3):140-52.
- Bayol SA, Simbi BH, Bertrand JA et al. (2008) Offspring from mothers fed a ‘junk food’ diet in pregnancy and lactation exhibit exacerbated adiposity that is more pronounced in females. J Physiol 586, 3219– 3230.
- Bayol SA, Simbi BH, Fowkes RC et al. (2010) A maternal ‘junk food’ diet in pregnancy and lactation promotes nonalcoholic fatty liver disease in rat offspring. Endocrinology 151, 1451–1461.
- Huang DQ, El-Serag HB, Loomba R. Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 18, 223–238 (2021).
- Pase CS, Metz VG, Roversi K, Roversi K, Vey LT, Dias VT, Schons CF, de David Antoniazzi CT, Duarte T, Duarte M, Burger ME. Trans fat intake during pregnancy or lactation increases anxiety-like behavior and alters proinflammatory cytokines and glucocorticoid receptor levels in the hippocampus of adult offspring. Brain Res Bull. 2021 Jan;166:110-117.
- Karayiannis D, Kontogianni MD, Mendorou C, Douka L, Mastrominas M, Yiannakouris N. Association between adherence to the Mediterranean diet and semen quality parameters in male partners of couples attempting fertility. Hum Reprod. 2017 Jan;32(1):215-222.
- Watkins AJ, Dias I, Tsuro H, Allen D, Emes RD, Moreton J, Wilson R, Ingram RJM, Sinclair KD. Paternal diet programs offspring health through sperm- and seminal plasma-specific pathways in mice. Proc Natl Acad Sci U S A. 2018 Oct 2;115(40):10064-10069.
- Gapp K, Parada GE, Gross F, Corcoba A, Kaur J, Grau E, Hemberg M, Bohacek J, Miska EA. Single paternal dexamethasone challenge programs offspring metabolism and reveals multiple candidates in RNA-mediated inheritance. iScience. 2021 Jul 16;24(8):102870.
- Blackburn EH (1991) Structure and function of telomeres. Nature 350, 569–573.
- Oikawa S, Kawanishi S (1999) Site-specific DNA damage at GGG sequence by oxidative stress may accelerate telomere shortening. FEBS Lett 453, 365–368.
- Kawanishi S & Oikawa S (2004) Mechanism of telomere shortening by oxidative stress. Ann NY Acad Sci 1019, 278–284.
- Olivnikov AM (1971) Principle of marginotomy in template synthesis of polynucleotides. Dokl Akad Nauk SSSR 201, 1469–1499.
- Armanios M (2013) Telomeres and age-related disease: how telomere biology informs clinical paradigms. J Clin Inv 123, 996–1002.
- Greider CW, Blackburn EH (1996) Telomeres, telomerase and cancer. Sci Am 274, 92–97.
- Richter T, von Zglinicki T (2007) A continuous correlation between oxidative stress and telomere length in fibroblasts. Exp Gerontol 11, 1039–1042.
- von Zglinicki T (2002) Oxidative stress shortens telomeres. Trends Biochem Sci 7, 339–344.
- von Zglinicki T, Pilger R, Sitte N (2000) Accumulation of single-strand breaks is the major cause of telomere shortening in human fibroblasts. Free Radic Biol Med 28, 64–74.
- Honda S, Hjelmeland LM, Handa JT (2001) Oxidative stress-induced single-strand breaks in chromosomal telomeres of human retinal pigment epithelial cells in vitro. Invest Opthalmol Vis Sci 42, 2139–2144.
- Petersen S, Saretzki G, von Zglinicki T (1998) Preferential accumulation of single-stranded regions in telomeres of human fibroblasts. Exp Cell Res 239, 152–160.
- Harley CB, Fuchter AB, Greider CW (1990) Telomeres shorten during ageing of fibroblasts. Nature 345, 448–460.
- Sun Y, Wang Q, Zhang Y, Geng M, Wei Y, Liu Y, Liu S, Petersen RB, Yue J, Huang K, Zheng L. Multigenerational maternal obesity increases the incidence of HCC in offspring via miR-27a-3p. J Hepatol. 2020 Sep;73(3):603-615.
- Rodríguez-González GL, Reyes-Castro LA, Bautista CJ, Beltrán AA, Ibáñez CA, Vega CC, Lomas-Soria C, Castro-Rodríguez DC, Elías-López AL, Nathanielsz PW, Zambrano E. Maternal obesity accelerates rat offspring metabolic ageing in a sex-dependent manner. J Physiol. 2019 Dec;597(23):5549-5563.
- Longo VD, Mattson MP. Fasting: Molecular Mechanisms and Clinical Applications. Cell metabolism. 2014;19:181–192.
- Wasselin T, Zahn S, Maho YL, Dorsselaer AV, Raclot T, Bertile F. Exacerbated oxidative stress in the fasting liver according to fuel partitioning. Proteomics. 2014;14:1905–1921.
- Verweij M, van Ginhoven TM, Mitchell JR, Sluiter W, van den Engel S, Roest HP, Torabi E, Ijzermans JN, Hoeijmakers JH, de Bruin RW. Preoperative fasting protects mice against hepatic ischemia/reperfusion injury: mechanisms and effects on liver regeneration. Liver Transpl. 2011;17:695–704.
- Lee C, Safdie FM, Raffaghello L, Wei M, Madia F, Parrella E, Hwang D, Cohen P, Bianchi G, Longo VD. Reduced levels of IGF-I mediate differential protection of normal and cancer cells in response to fasting and improve chemotherapeutic index. Cancer research. 2010;70:1564–1572.
- Shi Y, Felley-Bosco E, Marti TM, Orlowski K, Pruschy M, Stahel RA. Starvation- induced activation of ATM/Chk2/p53 signaling sensitizes cancer cells to cisplatin. BMC Cancer. 2012;12:571.
- Brandhorst S, Choi IY, Wei M, Cheng CW, Sedrakyan S, Navarrete G, Dubeau L, Yap LP, Park R, Vinciguerra M, Di Biase S, Mirzaei H, Mirisola MG, Childress P, Ji L, Groshen S, Penna F, Odetti P, Perin L, Conti PS, Ikeno Y, Kennedy BK, Cohen P, Morgan TE, Dorff TB, Longo VD. A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan. Cell Metab. 2015 Jul 7;22(1):86-99.
- Choi IY, Piccio L, Childress P, Bollman B, Ghosh A, Brandhorst S, Suarez J, Michalsen A, Cross AH, Morgan TE, Wei M, Paul F, Bock M, Longo VD. A Diet Mimicking Fasting Promotes Regeneration and Reduces Autoimmunity and Multiple Sclerosis Symptoms. Cell Rep. 2016 Jun 7;15(10):2136-2146.
- Rangan P, Choi I, Wei M, Navarrete G, Guen E, Brandhorst S, Enyati N, Pasia G, Maesincee D, Ocon V, Abdulridha M, Longo VD. Fasting-Mimicking Diet Modulates Microbiota and Promotes Intestinal Regeneration to Reduce Inflammatory Bowel Disease Pathology. Cell Rep. 2019 Mar 5;26(10):2704-2719.e6.
- Di Biase S, Lee C, Brandhorst S, Manes B, Buono R, Cheng CW, Cacciottolo M, Martin-Montalvo A, de Cabo R, Wei M, Morgan TE, Longo VD. Fasting-Mimicking Diet Reduces HO-1 to Promote T Cell-Mediated Tumor Cytotoxicity. Cancer Cell. 2016 Jul 11;30(1):136-146.
- Carrasco-Benso MP, Rivero-Gutierrez B, Lopez-Minguez J, Anzola A, Diez-Noguera A, Madrid JA, Lujan JA, Martínez-Augustin O, Scheer FA, Garaulet M. Human adipose tissue expresses intrinsic circadian rhythm in insulin sensitivity. FASEB J. 2016 Sep;30(9):3117-23.
- Beccuti G, Monagheddu C, Evangelista A, Ciccone G, Broglio F, Soldati L, Bo S. Timing of food intake: Sounding the alarm about metabolic impairments? A systematic review. Pharmacol Res. 2017 Nov;125(Pt B):132-141.
- Gu C, Brereton N, Schweitzer A, Cotter M, Duan D, Børsheim E, Wolfe RR, Pham LV, Polotsky VY, Jun JC. Metabolic Effects of Late Dinner in Healthy Volunteers-A Randomized Crossover Clinical Trial. J Clin Endocrinol Metab. 2020 Aug 1;105(8):2789–802.
- Yoshioka N, Ishigami M, Watanabe Y, Sumi H, Doisaki M, Yamaguchi T, Ito T, Ishizu Y, Kuzuya T, Honda T, Ishikawa T, Haruta JI, Fujishiro M. Effect of weight change and lifestyle modifications on the development or remission of nonalcoholic fatty liver disease: sex-specific analysis. Sci Rep. 2020 Jan 16;10(1):481.
- Davinelli S, Willcox DC, Scapagnini G. Extending healthy ageing: nutrient sensitive pathway and centenarian population. Immun Ageing. 2012;9:9.
- Levine ME, Suarez JA, Brandhorst S, Balasubramanian P, Cheng CW, Madia F, Fontana L, Mirisola MG, Guevara-Aguirre J, Wan J, Passarino G, Kennedy BK, Wei M, Cohen P, Crimmins EM, Longo VD. Low protein intake is associated with a major reduction in IGF-1, cancer, and overall mortality in the 65 and younger but not older population. Cell Metab. 2014 Mar 4;19(3):407-17.
- Fontana L, Weiss EP, Villareal DT, Klein S, Holloszy JO. Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humans. Aging cell. 2008;7:681–687.
- Brandhorst S, Longo VD. Protein Quantity and Source, Fasting-Mimicking Diets, and Longevity. Adv Nutr. 2019 Nov 1;10(Suppl_4):S340-S350.
- Green CL, Lamming DW, Fontana L. Molecular mechanisms of dietary restriction promoting health and longevity. Nat Rev Mol Cell Biol. 2021 Sep 13. doi: 10.1038/s41580-021-00411-4.
- National Cancer Institute. Chemicals in Meat Cooked at High Temperatures and Cancer Risk. https://www.cancer.gov/about-cancer/causes-prevention/risk/diet/cooked-meats-fact-sheet
- Yang Y, Zhao LG, Wu QJ, Ma X, Xiang YB. Association between dietary fiber and lower risk of all-cause mortality: A Meta-Analysis of Cohort Studies. Am J Epidemiol. 2015;181:83-91.
- Zhang G, Li J, Purkayastha S, Tang Y, Zhang H, Yin Y, Li B, Liu G, Cai D. Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH. Nature. 2013 May 9;497(7448):211-6.
- Kim K, Choe HK. Role of hypothalamus in aging and its underlying cellular mechanisms. Mech Ageing Dev. 2019 Jan;177:74-79.
- Redman L.M., Fontana L. Calorie restriction in humans: An update. Ageing Res. Rev. 2017 Oct;39:36-45.
- Kumsta C, Chang J, Schmalz J, Hansen M. Hormetic heat stress and HSF-1 induce autophagy to improve survival and proteostasis in C. elegans. Nat Commun 8, 14337 (2017).