Life Extension Magazine®

Scientist studying effects of caloric restrictions on senescent cells

Nutrients that Provide Benefits of Caloric Restriction

Caloric restriction extends healthy lifespans. Researchers have identified plant-derived compounds that activate similar cellular responses.

Scientifically reviewed by: Dr. Crystal M. Gossard, DCN, CNS, LDN, in October 2024. Written by: Nancy Kovacs.

 

Published studies on a wide range of organisms show:

Caloric restriction can improve health and extend life.1-3

But people are challenged when trying to chronically reduce their food intake.1

Even those who initially succeed often return to regular eating, losing out on the longevity benefits that caloric restriction can offer.

Researchers have identified plant-derived compounds that help activate similar health-promoting cellular responses as caloric restriction.

How Caloric Restriction Prolongs Life

Gynostemma pentaphyllum leaf

Caloric restriction means limiting the number of calories consumed each day, while avoiding malnutrition.

Restricting calories extends life and reduces age-related chronic disease in many organisms.2,3 These effects have been observed in a wide range of animal models, including mammals.

When caloric intake is low, during what’s known as a fasting state, cells switch into protective mode. They activate processes that rejuvenate themselves and defend against potential threats and stressors.

These changes have long-term benefits for overall health, and possibly for life extension as well.

On the flip side is the dietary excess plaguing modern societies. This chronic, surplus calorie ingestion contributes to a variety of health problems.

Surging rates of obesity, type II diabetes, neurodegenerative disorders, and cancer have all been linked to excessive calorie intake.

Scientists have pinpointed some of the specific cellular changes that occur with caloric restriction. The most practical ways of achieving these benefits are:4-10

1. Boosting function of sirtuins, proteins that regulate cellular health,

2. Increasing activity of AMPK, an enzyme that regulates metabolism,

3. Reducing activity of mTOR, a protein linked to aging and chronic disease,

4. Blocking cellular senescence, when older cells become dysfunctional, and

5. Encouraging autophagy, cellular “housekeeping.”

These actions protect against many forms of chronic disease and accelerated aging.4,6-10

Caloric Restriction and Intermittent Fasting “Mimetics”

Sticking to a restrictive diet is difficult.

It can also be unpleasant. For some, substantial caloric restriction may lead to loss of strength and stamina, loss of libido, loss of bone density, depression, and other undesirable effects.1

Research is increasingly finding that there are alternatives to severe dietary restriction. Several compounds have been shown to target some of the same cellular pathways as caloric restriction, without side effects.5,7-9,11

These compounds are known as caloric restriction mimetics. A mimetic is something that mimics the effects of something else.

Some of the nutrients found to be caloric restriction mimetics are health-promoting polyphenols.

For each of the five major cellular changes spurred by caloric restriction, science has discovered mimetics that have the same effects.

1. Boosting Sirtuin Function

Husband and wife making dinner

One way caloric restriction extends lifespan is by ramping up the activity of signaling proteins called sirtuins, particularly SIRT1.6-8

Sirtuins regulate cellular health and defend cellular components in times of stress. They shield DNA from damage that speeds the aging process and makes cells susceptible to disease.12,13

Studies show that improving sirtuin function extends lifespan of various organisms.12,14-18

The polyphenol resveratrol, found in minute quantities in red wine, grapes, and berries, activates SIRT1.14-16,19,20

In mice, resveratrol helps mimic the changes induced by dietary restriction, reducing the signs of aging.11

Resveratrol has been shown to stabilize DNA and extend lifespan of yeast by a whopping 70%.19

While resveratrol activates sirtuins, a cofactor called NAD+ (nicotinamide adenine dinucleotide) is required for sirtuins to function properly. With advancing age, NAD+ levels drop.12,13

The oral NAD+ precursor nicotinamide riboside boosts NAD+ cellular levels rapidly, helping to support healthy sirtuin function.21-23

Taken together, resveratrol and nicotinamide riboside maximize the benefits for cellular health and longevity.

2. Activating AMPK

Another longevity-promoting change spurred by caloric restriction is increased activity of an enzyme called AMPK.

Stimulating AMPK has a critical impact on metabolism. It helps prevent weight gain, improves insulin sensitivity, and reduces high blood glucose levels.24-27

The most commonly prescribed medication for type II diabetes is metformin, which works partially by activating AMPK.

A number of plant-derived compounds are also potent activators of AMPK.

Gynostemma pentaphyllum is known as the “immortality herb” in some Asian cultures. Cell and animal studies have shown that Gynostemma extracts activate AMPK, resulting in health benefits that include reduced body weight and improved cholesterol levels.28-32

In a 2019 study of mice fed an obesity-inducing diet, Gynostemma prevented weight gain, reduced fat mass, and improved blood lipid markers.33

AMPK also stimulates SIRT1. In this 2019 study, animals receiving Gynostemma had an approximately 4.5-fold increase in SIRT1 expression compared to untreated animals.

Hesperidin is a plant compound found in citrus fruits that has also been shown to amplify AMPK activity.34-37 In mice, it lowers body weight and lipid levels while improving insulin sensitivity and glucose control.35

In humans, 500 mg of hesperidin daily was found to lead to improvements including better blood vessel reactivity and reduced body-wide inflammation.36

What you need to know

The Benefits of Caloric Restriction Without Fasting

  • Caloric restriction has powerful anti-aging effects, reducing chronic disease and extending life, as shown in many studies.
  • Restrictive diets are difficult to adhere to and have potential unpleasant side effects.
  • Scientists have identified crucial cell changes that are induced by dietary restriction. These include sirtuin activation, boosting AMPK, reducing mTOR activity, protecting against cell senescence, and promoting beneficial autophagy.
  • Several plant-derived nutrients mimic the cellular effects of restricting calories, producing some of the same protective benefits.
  • Resveratrol, nicotinamide riboside, Gynostemma pentaphyllum, hesperidin, curcumin, quercetin, theaflavins, and apigenin are nutrients that closely imitate the beneficial effects of restrictive diets.

3. Decreasing mTOR Activity

mTOR stands for the “mechanistic target of rapamycin.”

In youth, balanced mTOR activity enables rapid growth.

If mTOR activity remains stuck in high gear as people age, it contributes to a number of deleterious effects.

When nutrients are plentiful, mTOR activity goes up.

If mTOR is not balanced, aging individuals could accumulate unwanted fat stores even when they don’t ingest calories excessively.

Caloric restriction decreases mTOR activity, protecting health.8

Research shows that resveratrol and curcumin, a compound found in turmeric root, have mTOR-inhibiting activity.38-42

4. Preventing Cellular Senescence

Senescent cells that promote inflammation

As cells age, many become dysfunctional and lose the ability to grow or divide. This is referred to as cellular senescence.

Senescent cells secrete compounds that damage surrounding cells and promote chronic inflammation.

Cellular senescence is a major driver of aging of tissues, loss of function, and development of disease.

Caloric restriction limits the development of senescent cells, shielding tissues from their harmful effects.6

Compounds called senolytics can help reduce the senescent cells’ burdens without caloric restriction.

The most studied senolytic therapy combines the plant pigment quercetin, found in many fruits and vegetables, with the chemotherapy drug dasatinib.

Several studies show this two-compound cocktail (dasatinib + quercetin) decreases the number of senescent cells in tissues, reducing signs of aging and diminishing the occurrence and severity of chronic disease.48-51

Early human trials of this therapy are showing promising results, but dasatinib is a synthetic pharmaceutical drug.48,52 As a result, many people today would prefer a safer senolytic compound.

Scientists have found another way to remove senescent cells, using plant-based nutrients found in commonly consumed food and beverages.

Quercetin on its own possesses senolytic properties,53 and theaflavins from black tea act in similar cell signalling ways as dasatinib.54-56

Recently, researchers have made another advance in senolytic therapy. They’ve found that apigenin (a plant compound) reduces harmful compounds that senescent cells emit.57,58

By combining a highly absorbable quercetin with theaflavins and apigenin, scientists have created a plant-based formula, available without a prescription, that provides senolytic action without resorting to pharmaceutical drugs.

And even more exciting is the advent of bioavailable fisetin that may be the most effective way to remove senescent cells from aging bodies. Look forward to a novel and low-cost bioavailable fisetin in the near future.

5. Enhancing Autophagy

As cells get older, they accumulate damaged and worn-out components that interfere with the proper functioning of the cell.

In earlier stages of their life, cells do a kind of “housekeeping” on a regular basis. This involves removing older, damaged components inside cells and replacing them with new, healthy components. This process is referred to as autophagy.

With advancing age and poor diet, autophagy declines and cell clutter builds up, robbing tissues of their healthy cellular function. Deficient autophagy contributes to many diseases of older age.59

Caloric restriction has been shown to stimulate autophagy, refreshing and rejuvenating cells.4

A number of nutrients found in plants, particularly resveratrol and curcumin, have also been shown to stimulate healthy autophagy.59-63

Studies indicate this has protective effects against cancer, neurodegenerative disorders like Alzheimer’s disease, and other chronic diseases.59-63

Look forward to specific plant-derived autophagy-inducers being introduced in 2021. In the meantime, it’s good to know that nutrients most readers of this magazine already supplement with have internal cell-cleansing properties.

Summary

Couple looking at recipe for caloric restriction

Caloric restriction is one of the most widely studied methods to prevent disease and extend lifespan.

For people, adhering to rigorous dietary regimens can be difficult, if not impossible.

Scientists have identified cellular processes that are favorably altered by calorie-restricting diets.

Several plant-derived nutrients have been shown to mimic many of the effects of dietary restriction.

Resveratrol and nicotinamide riboside boost and maintain healthy levels of protective sirtuin function.

Gynostemma pentaphyllum and hesperidin activate the metabolism-regulating enzyme AMPK.

Resveratrol and curcumin limit harmful activity of the protein mTOR, while stimulating autophagy, or cellular “housekeeping.”

Theaflavins and highly absorbable quercetin reduce the numbers of old, dysfunctional senescent cells in tissues. And apigenin reduces harmful compounds that senescent cells emit.

These effects help mimic the longevity-promoting impact of caloric restriction.

If you have any questions on the scientific content of this article, please call a Life Extension® Wellness Specialist at 1-866-864-3027.

References

  1. Dirks AJ, Leeuwenburgh C. Caloric restriction in humans: potential pitfalls and health concerns. Mech Ageing Dev. 2006 Jan;127(1):1-7.
  2. Anton S, Leeuwenburgh C. Fasting or caloric restriction for healthy aging. Exp Gerontol. 2013 Oct;48(10):1003-5.
  3. Golbidi S, Daiber A, Korac B, et al. Health Benefits of Fasting and Caloric Restriction. Curr Diab Rep. 2017 Oct 23;17(12):123.
  4. Bergamini E, Cavallini G, Donati A, et al. The role of autophagy in aging: its essential part in the anti-aging mechanism of caloric restriction. Ann N Y Acad Sci. 2007 Oct;1114:69-78.
  5. Calvert S, Tacutu R, Sharifi S, et al. A network pharmacology approach reveals new candidate caloric restriction mimetics in C. elegans. Aging Cell. 2016 Apr;15(2):256-66.
  6. Fontana L, Nehme J, Demaria M. Caloric restriction and cellular senescence. Mech Ageing Dev. 2018 Dec;176:19-23.
  7. Lee SH, Min KJ. Caloric restriction and its mimetics. BMB Rep. 2013 Apr;46(4):181-7.
  8. Madeo F, Carmona-Gutierrez D, Hofer SJ, et al. Caloric Restriction Mimetics against Age-Associated Disease: Targets, Mechanisms, and Therapeutic Potential. Cell Metab. 2019 Mar 5;29(3):592-610.
  9. Roth GS, Ingram DK. Manipulation of health span and function by dietary caloric restriction mimetics. Ann N Y Acad Sci. 2016 Jan;1363:5-10.
  10. Ungvari Z, Parrado-Fernandez C, Csiszar A, et al. Mechanisms underlying caloric restriction and lifespan regulation: implications for vascular aging. Circ Res. 2008 Mar 14;102(5):519-28.
  11. Pearson KJ, Baur JA, Lewis KN, et al. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab. 2008 Aug;8(2):157-68.
  12. Imai S, Guarente L. NAD+ and sirtuins in aging and disease. Trends Cell Biol. 2014 Aug;24(8):464-71.
  13. Johnson S, Imai SI. NAD (+) biosynthesis, aging, and disease. F1000Res. 2018;7:132.
  14. Cao MM, Lu X, Liu GD, et al. Resveratrol attenuates type 2 diabetes mellitus by mediating mitochondrial biogenesis and lipid metabolism via Sirtuin type 1. Exp Ther Med. 2018 Jan;15(1):576-84.
  15. Cao W, Dou Y, Li A. Resveratrol Boosts Cognitive Function by Targeting SIRT1. Neurochem Res. 2018 Sep;43(9):1705-13.
  16. Deng Z, Li Y, Liu H, et al. The role of sirtuin 1 and its activator, resveratrol in osteoarthritis. Biosci Rep. 2019 May 31;39(5).
  17. Belenky P, Racette FG, Bogan KL, et al. Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/Meu1 pathways to NAD+. Cell. 2007 May 4;129(3):473-84.
  18. Zhang H, Ryu D, Wu Y, et al. NAD(+) repletion improves mitochondrial and stem cell function and enhances life span in mice. Science. 2016 Jun 17;352(6292):1436-43.
  19. Alcain FJ, Villalba JM. Sirtuin activators. Expert Opin Ther Pat. 2009 Apr;19(4):403-14.
  20. Kaeberlein M, McDonagh T, Heltweg B, et al. Substrate-specific activation of sirtuins by resveratrol. J Biol Chem. 2005 Apr 29;280(17):17038-45.
  21. Martens CR, Denman BA, Mazzo MR, et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD(+) in healthy middle-aged and older adults. Nat Commun. 2018 Mar 29;9(1):1286.
  22. Trammell SA, Schmidt MS, Weidemann BJ, et al. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun. 2016 Oct 10;7:12948.
  23. Yang T, Chan NY, Sauve AA. Syntheses of nicotinamide riboside and derivatives: effective agents for increasing nicotinamide adenine dinucleotide concentrations in mammalian cells. J Med Chem. 2007 Dec 27;50(26):6458-61.
  24. Lyons CL, Roche HM. Nutritional Modulation of AMPK-Impact upon Metabolic-Inflammation. Int J Mol Sci. 2018 Oct 9;19(10).
  25. Ruderman NB, Carling D, Prentki M, et al. AMPK, insulin resistance, and the metabolic syndrome. J Clin Invest. 2013 Jul;123(7):2764-72.
  26. Salminen A, Kaarniranta K. AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing Res Rev. 2012 Apr;11(2):230-41.
  27. Towler MC, Hardie DG. AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res. 2007 Feb 16;100(3):328-41.
  28. Gauhar R, Hwang SL, Jeong SS, et al. Heat-processed Gynostemma pentaphyllum extract improves obesity in ob/ob mice by activating AMP-activated protein kinase. Biotechnol Lett. 2012 Sep;34(9):1607-16.
  29. Nguyen PH, Gauhar R, Hwang SL, et al. New dammarane-type glucosides as potential activators of AMP-activated protein kinase (AMPK) from Gynostemma pentaphyllum. Bioorg Med Chem. 2011 Nov 1;19(21):6254-60.
  30. Park SH, Huh TL, Kim SY, et al. Antiobesity effect of Gynostemma pentaphyllum extract (actiponin): a randomized, double-blind, placebo-controlled trial. Obesity (Silver Spring). 2014 Jan;22(1):63-71.
  31. Wang J, Ha TKQ, Shi YP, et al. Hypoglycemic triterpenes from Gynostemma pentaphyllum. Phytochemistry. 2018 Nov;155:171-81.
  32. Dong C, Xie Z, Yu Y, et al. Discovery, synthesis, and structure-activity relationships of 20S-dammar-24-en-2alpha,3beta,12beta,20-tetrol (GP) derivatives as a new class of AMPKalpha2beta1gamma1 activators. Bioorg Med Chem. 2016 Jun 15;24(12):2688-96.
  33. Lee HS, Lim SM, Jung JI, et al. Gynostemma Pentaphyllum Extract Ameliorates High-Fat Diet-Induced Obesity in C57BL/6N Mice by Upregulating SIRT1. Nutrients. 2019 Oct 15;11(10).
  34. Ohara T, Muroyama K, Yamamoto Y, et al. Oral intake of a combination of glucosyl hesperidin and caffeine elicits an anti-obesity effect in healthy, moderately obese subjects: a randomized double-blind placebo-controlled trial. Nutr J. 2016 Jan 19;15:6.
  35. Pu P. [Protection mechanisms of hesperidin on mouse with insulin resistance]. Zhongguo Zhong Yao Za Zhi. 2016 Sep;41(17):3290-5.
  36. Rizza S, Muniyappa R, Iantorno M, et al. Citrus polyphenol hesperidin stimulates production of nitric oxide in endothelial cells while improving endothelial function and reducing inflammatory markers in patients with metabolic syndrome. J Clin Endocrinol Metab. 2011 May;96(5):E782-92.
  37. Xiong H, Wang J, Ran Q, et al. Hesperidin: A Therapeutic Agent For Obesity. Drug Des Devel Ther. 2019;13:3855-66.
  38. Beevers CS, Chen L, Liu L, et al. Curcumin disrupts the Mammalian target of rapamycin-raptor complex. Cancer Res. 2009 Feb 1;69(3):1000-8.
  39. Kuo CJ, Huang CC, Chou SY, et al. Potential therapeutic effect of curcumin, a natural mTOR inhibitor, in tuberous sclerosis complex. Phytomedicine. 2019 Feb 15;54:132-9.
  40. Liu M, Wilk SA, Wang A, et al. Resveratrol inhibits mTOR signaling by promoting the interaction between mTOR and DEPTOR. J Biol Chem. 2010 Nov 19;285(47):36387-94.
  41. Zhou H, Luo Y, Huang S. Updates of mTOR inhibitors. Anticancer Agents Med Chem. 2010 Sep;10(7):571-81.
  42. Huang S. Inhibition of PI3K/Akt/mTOR signaling by natural products. Anticancer Agents Med Chem. 2013 Sep;13(7):967-70.
  43. Den Hartogh DJ, Gabriel A, Tsiani E. Antidiabetic Properties of Curcumin II: Evidence from In Vivo Studies. Nutrients. 2019 Dec 25;12(1).
  44. Den Hartogh DJ, Gabriel A, Tsiani E. Antidiabetic Properties of Curcumin I: Evidence from In Vitro Studies. Nutrients. 2020 Jan 1;12(1).
  45. Lu X, Wu F, Jiang M, et al. Curcumin ameliorates gestational diabetes in mice partly through activating AMPK. Pharm Biol. 2019 Dec;57(1):250-4.
  46. Repossi G, Das UN, Eynard AR. Molecular Basis of the Beneficial Actions of Resveratrol. Arch Med Res. 2020 Feb;51(2):105-14.
  47. Song J, Huang Y, Zheng W, et al. Resveratrol reduces intracellular reactive oxygen species levels by inducing autophagy through the AMPK-mTOR pathway. Front Med. 2018 Dec;12(6):697-706.
  48. Hickson LJ, Langhi Prata LGP, Bobart SA, et al. Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine. 2019 Sep;47:446-56.
  49. Palmer AK, Xu M, Zhu Y, et al. Targeting senescent cells alleviates obesity-induced metabolic dysfunction. Aging Cell. 2019 Jun;18(3):e12950.
  50. Zhang P, Kishimoto Y, Grammatikakis I, et al. Senolytic therapy alleviates Abeta-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat Neurosci. 2019 May;22(5):719-28.
  51. Zhu Y, Tchkonia T, Pirtskhalava T, et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015 Aug;14(4):644-58.
  52. Justice JN, Nambiar AM, Tchkonia T, et al. Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. EBioMedicine. 2019 Feb;40:554-63.
  53. Kim SR, Jiang K, Ogrodnik M, et al. Increased renal cellular senescence in murine high-fat diet: effect of the senolytic drug quercetin. Transl Res. 2019 Nov;213:112-23.
  54. Han X, Zhang J, Xue X, et al. Theaflavin ameliorates ionizing radiation-induced hematopoietic injury via the NRF2 pathway. Free Radic Biol Med. 2017 Dec;113:59-70.
  55. Noberini R, Koolpe M, Lamberto I, et al. Inhibition of Eph receptor-ephrin ligand interaction by tea polyphenols. Pharmacol Res. 2012 Oct;66(4):363-73.
  56. Noberini R, Lamberto I, Pasquale EB. Targeting Eph receptors with peptides and small molecules: progress and challenges. Semin Cell Dev Biol. 2012 Feb;23(1):51-7.
  57. Lim H, Park H, Kim HP. Effects of flavonoids on senescence-associated secretory phenotype formation from bleomycin-induced senescence in BJ fibroblasts. Biochem Pharmacol. 2015 Aug 15;96(4):337-48.
  58. Perrott KM, Wiley CD, Desprez PY, et al. Apigenin suppresses the senescence-associated secretory phenotype and paracrine effects on breast cancer cells. Geroscience. 2017 Apr;39(2):161-73.
  59. Forouzanfar F, Read MI, Barreto GE, et al. Neuroprotective effects of curcumin through autophagy modulation. IUBMB Life. 2020 Apr;72(4):652-64.
  60. Deng S, Shanmugam MK, Kumar AP, et al. Targeting autophagy using natural compounds for cancer prevention and therapy. Cancer. 2019 Apr 15;125(8):1228-46.
  61. Kou X, Chen N. Resveratrol as a Natural Autophagy Regulator for Prevention and Treatment of Alzheimer’s Disease. Nutrients. 2017 Aug 24;9(9).
  62. Lin KL, Lin KJ, Wang PW, et al. Resveratrol provides neuroprotective effects through modulation of mitochondrial dynamics and ERK1/2 regulated autophagy. Free Radic Res. 2018 Dec;52(11-12):1371-86.
  63. Perrone L, Squillaro T, Napolitano F, et al. The Autophagy Signaling Pathway: A Potential Multifunctional Therapeutic Target of Curcumin in Neurological and Neuromuscular Diseases. Nutrients. 2019 Aug 13;11(8).