Tag Archives: CR

Fasting Without Calorie Restriction Extends Lifespan

Join us on Patreon!
https://www.patreon.com/MichaelLustgartenPhD

Bristle Discount Link (Oral microbiome quantification):
ConquerAging15

https://www.bmq30trk.com/4FL3LK/GTSC3/

Cronometer Discount Link (Daily diet tracking):
https://shareasale.com/r.cfm?b=1390137&u=3266601&m=61121&urllink=&afftrack=

Support the channel with Buy Me A Coffee!
https://www.buymeacoffee.com/mlhnrca


Paper referenced in the video:
Daily Fasting Improves Health and Survival in Male Mice Independent of Diet Composition and Calories
https://pubmed.ncbi.nlm.nih.gov/30197301/

High FGF21, Low Insulin And Glucose: A Pro-Longevity Strategy?

Papers referenced in the video:

FGF21 and Chronic Kidney Disease: https://www.sciencedirect.com/science…

The starvation hormone, fibroblast growth factor-21, extends lifespan in mice: https://www.ncbi.nlm.nih.gov/pmc/arti…

Inhibition of growth hormone signaling by the fasting-induced hormone FGF21: https://pubmed.ncbi.nlm.nih.gov/18585…

Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice: https://pubmed.ncbi.nlm.nih.gov/32877…

Berberine ameliorates cellular senescence and extends the lifespan of mice via regulating p16 and cyclin protein expression: https://pubmed.ncbi.nlm.nih.gov/31773…

Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice: https://www.ncbi.nlm.nih.gov/pmc/arti…

Regulation of longevity by FGF21: Interaction between energy metabolism and stress responses: https://pubmed.ncbi.nlm.nih.gov/28552…

Disease-specific plasma levels of mitokines FGF21, GDF15, and Humanin in type II diabetes and Alzheimer’s disease in comparison with healthy aging: https://pubmed.ncbi.nlm.nih.gov/33131…

Aging is associated with increased FGF21 levels but unaltered FGF21 responsiveness in adipose tissue: https://pubmed.ncbi.nlm.nih.gov/30043…

Circulating levels of fibroblast growth factor-21 increase with age independently of body composition indices among healthy individuals: https://pubmed.ncbi.nlm.nih.gov/26042…

Lower All-Cause, Cardiovascular, and Cancer Mortality in Centenarians’ Offspring: https://pubmed.ncbi.nlm.nih.gov/15571…

Favorable Glucose Tolerance and Lower Prevalence of Metabolic Syndrome in Offspring without Diabetes Mellitus of Nonagenarian Siblings: The Leiden Longevity Study: https://pubmed.ncbi.nlm.nih.gov/20398…

CD38 Gets In The Way Of NR And NMN For Increasing NAD+

NR and NMN are popular ways to try to boost levels of NAD+, but that approach hasn’t worked every time in human studies. One reason for that may involve CD38, which degrades both NR and NMN. With the goal of boosting NAD+ levels during aging, why does CD38 increase with age, and what can be done about it? All that and more in this video!

Optimizing Biological Age: White Blood Cells

Circulating levels of white blood cells (WBCs) are one of the 10 variables used to quantify biological age with PhenoAge (https://atomic-temporary-71218033.wpcomstaging.com/2019/09/09/quantifying-biological-age). The reference range for WBCs is 4.5 – 11 *10^9 cells/L, but within that range, what’s optimal?

Several studies have reported that WBCs greater than 5 are associated with an increased all-cause mortality risk (Ahmadi-Abhari et al. 2013, Samet et al. 2005, Weijenberg et al. 1996). While observational studies are important for identifying associations with mortality risk, stronger evidence is obtained when the data from the same subjects are tracked for a long time period. Perhaps the best evidence for the association between WBCs with mortality risk comes from the Baltimore Longitudinal Study on Aging (BLSA), which studied 2803 men and women over a period of 44 years (Ruggiero et al. 2007). As shown below, subjects that had circulating WBCs between 3.5 – 6 had the best survival, whereas WBCs below 3.5, between 6 – 10, and 10+ each had successively higher risk. The 0.5 point on the y-axis of the curve (survival) is defined as 50% mortality, and is the point where half of the study subjects died, whereas the remaining 50% were still alive. At that point, compared with subjects that had WBCs between 6 – 10, people that had WBCs between 3.5 – 6 lived ~7 years longer! So getting your WBC into that range may be a big deal for increasing life expectancy.

wbc ferr

How can you reduce circulating WBCs? One way to reduce WBCs is to eat less calories, thereby reducing your body weight. As shown below, eating less calories resulted in a decreased BMI and decreased WBCs in the Biosphere II project (Walford et al. 2002), almost exactly in the same pattern:

cr bmi

WBC Biosphere

Because calorie restriction reduced WBCs from ~6.8 to 4.6, should 4.6 be considered optimal? In support of this idea, calorie restriction is well documented to increase lifespan in a variety of organisms, including flies, worms, and rodents. Although there isn’t any evidence (yet) on the long-term effects of calorie restriction (CR) on lifespan in people, it has been shown to be protective against age-related diseases, including abdominal obesity, diabetes, hypertension, and cardiovascular disease (Omodei and Fontana 2011). Therefore, a reduced WBC level may be related to the positive health-related effects of CR. 

As an argument against using the CR-mediated reduction in WBC as a guide for what the optimal range should be, calorically-restricted mice have a decreased survival in response to infection (Goldberg et al. 2015):

cr survival

However, it’s important to note that infection-related survival was decreased in CR mice that were 40% restricted in terms of daily calories. Based on the Biosphere 2 data above, BMI was reduced from ~23 to 19, which translates into a 17% reduction. However, whether 17% CR is better for improving infection-related survival compared with 40% CR is currently unknown.

What’s my WBC level? Shown below is my WBC data for the past 16 years, including 25 measurements (average WBCs, 4.78 * 10^9 cells/L). The 2 red lines delineate the 3.5 – 6 range that was associated with an increased lifespan in the BLSA study (Ruggiero et al. 2007), and based on that, I’ve only had 1 measurement that was higher than that range.

wbc update

Starting from the red arrow below, WBCs increase during the 22-year period that precedes death (Ruggiero et al. 2007), so making sure that they don’t go up during aging is important!

wbc age

 

If you’re interested, please have a look at my book!

 

References

Ahmadi-Abhari S, Luben RN, Wareham NJ, Khaw KT. Seventeen year risk of all-cause and cause-specific mortality associated with C-reactive proteinfibrinogen and leukocyte count in men and women: the EPIC-Norfolk studyEur J Epidemiol. 2013 Jul;28(7):541-50.

Goldberg EL, Romero-Aleshire MJ, Renkema KR, Ventevogel MS, Chew WM, Uhrlaub JL, Smithey MJ, Limesand KH, Sempowski GD, Brooks HL, Nikolich-Žugich J. Lifespan-extending caloric restriction or mTOR inhibition impair adaptive immunity of old mice by distinct mechanisms. Aging Cell. 2015 Feb;14(1):130-8.

Jee SH, Park JY, Kim HS, Lee TY, Samet JM. White blood cell count and risk for all-causecardiovascular, and cancer mortality in a cohort of KoreansAm J Epidemiol. 2005 Dec 1;162(11):1062-9.

Omodei D, Fontana L. Calorie restriction and prevention of age-associated chronic diseaseFEBS Lett. 2011 Jun 6;585(11):1537-42.

Ruggiero C, Metter EJ, Cherubini A, Maggio M, Sen R, Najjar SS, Windham GB, Ble A, Senin U, Ferrucci L. White blood cell count and mortality in the Baltimore Longitudinal Study of AgingJ Am Coll Cardiol. 2007 May 8;49(18):1841-50.

Walford RL, Mock D, Verdery R, MacCallum T. Calorie restriction in biosphere 2: alterations in physiologic, hematologic, hormonal, and biochemical parameters in humans restricted for a 2-year period. J Gerontol A Biol Sci Med Sci. 2002 Jun;57(6):B211-24.

Weijenberg MP, Feskens EJ, Kromhout D. White blood cell count and the risk of coronary heart disease and all-cause mortality in elderly menArterioscler Thromb Vasc Biol. 1996 Apr;16(4):499-503.

Blood testing: What’s optimal for WBC levels?

My approach towards optimal health involves yearly blood testing and tracking my results to catch changes before they become problematic. In this article, I will evaluate the published literature to propose an optimal range for circulating white blood cells (WBC).

Why is measuring WBCs important? Briefly, circulating WBCs are correlated with inflammation- inflammation increases during aging, is associated with decreased function of multiple organ systems, and is associated with an increased chronic disease risk (Cevenini et al. 2013).

As shown below, Huang et al. (2007) reported significant correlations between circulating WBCs with a marker of inflammation, C-reactive protein (CRP). This correlation was statistically significant in the whole population (14,114 subjects), in subjects older than or less than 50 years, and separately in men and women.

crp wbc

Based on that data, Huang et al. (2007) suggested changing the reference range (8 years ago!) for WBCs from 4-11 to 3.11-8.83 K/mm3. But within that range, what’s optimal for health and longevity? Because WBC are elevated in association with inflammation, the hypothesis would be that the lower end of the range is better, with values ~4 being optimal. Is this true?

Several studies have reported that WBC values greater than 5 are associated with an increased all-cause mortality risk (Ahmadi-Abhari et al. 2013, Samet et al. 2005, Weijenberg et al. 1996). However, the best evidence for the association between WBCs with mortality risk comes from the Baltimore Longitudinal Study on Aging (BLSA), which studied 2803 men and women over a period of 44 years (Ruggiero et al. 2007). As shown below, subjects that had circulating WBC between 3.5 and 6 had decreased mortality risk, whereas below 3.5, between 6-10, and 10+ each had successively higher risk. The 0.5 point on the y-axis of the curve (survival) is defined as 50% mortality, where half of the study subjects have died. At that point, compared with subjects with WBC values between 6-10, people with values between 3.5 and 6 live ~7 years longer! So getting your WBC into that range may be a big deal for living significantly longer.

wbc ferr

How can you reduce circulating WBCs? One way to reduce WBCs is to eat less calories, thereby reducing your body weight. As shown below, eating less calories resulted in decreased BMI and decreased WBCs in the Biosphere II project (Walford et al. 2002), almost exactly in the same pattern:

cr bmi

WBC Biosphere

Because calorie restriction reduced WBCs from ~6.8 to 4.6, should 4.6 be considered optimal? In support of this idea, calorie restriction is well documented to increase lifespan in a variety of organisms, including flies, worms, and rodents. Although there isn’t any evidence on the long-term effects of calorie restriction (CR) on lifespan in people, it has been shown to be protective against age-related diseases, including abdominal obesity, diabetes, hypertension, and cardiovascular disease (Omodei and Fontana 2011). Therefore, a reduced WBC level may be related to the positive health-related effects of CR. 

As an argument against using the CR-mediated reduction in WBC as a guide for what the optimal range should be, calorically restricted mice have decreased infection-related survival (Goldberg et al. 2015):

cr survival

However, it’s important to note that infection-related survival was decreased in adult CR mice that were 40% restricted in terms of daily calories. Based on the Biosphere 2 data above, BMI was reduced from ~23 to 19, which translates into an ~18% reduction in BMI. However, whether 18% CR is better for improving infection-related survival compared with 40% CR is currently unknown.

What’s my WBC level? My lowest WBC value was in 2008, at 3.9. In 4 measurements from 2008-2013 my WBC increased to 4.4, 4.6, 5.7, and 5.9. However, in my most recent blood test, they’re back down to 4.4. I have 2 possible explanations for reducing my age-related increase in WBCs. First, my body weight weight is ~10 lbs less since last year,  and my 100g+ fiber diet may improve gut barrier function to keep bacteria and other stuff out of my blood that shouldn’t be there, thereby decreasing my systemic immune response.

wbc

My recent 4.4 WBC value puts me close to the CR-value (4.6), and within the optimal 3.5-6 range identified in the BLSA study. So far so good! Stay tuned for the data next year to see if my WBCs remain low or start to rise again.

If you’re interested, please have a look at my book!

References

Ahmadi-Abhari S, Luben RN, Wareham NJ, Khaw KT. Seventeen year risk of all-cause and cause-specific mortality associated with C-reactive proteinfibrinogen and leukocyte count in men and women: the EPIC-Norfolk studyEur J Epidemiol. 2013 Jul;28(7):541-50.

Cevenini E, Caruso C, Candore G, Capri M, Nuzzo D, Duro G, Rizzo C, Colonna-Romano G, Lio D, Di Carlo D, Palmas MG, Scurti M, Pini E, Franceschi C, Vasto S. Age-related inflammation: the contribution of different organs, tissues and systems. How to face it for therapeutic approaches. Curr Pharm Des. 2010;16(6):609-18.

Goldberg EL, Romero-Aleshire MJ, Renkema KR, Ventevogel MS, Chew WM, Uhrlaub JL, Smithey MJ, Limesand KH, Sempowski GD, Brooks HL, Nikolich-Žugich J. Lifespan-extending caloric restriction or mTOR inhibition impair adaptive immunity of old mice by distinct mechanisms. Aging Cell. 2015 Feb;14(1):130-8.

Huang ZS, Lo SC, Tsay W, Hsu KL, Chiang FT. Revision in referene ranges of peripheral total leukocyte count and differential leukocyte percentages based on a normal serum C-reactive protein level. J Formos Med Assoc. 2007 Aug;106(8):608-16.

Jee SH, Park JY, Kim HS, Lee TY, Samet JM. White blood cell count and risk for all-causecardiovascular, and cancer mortality in a cohort of KoreansAm J Epidemiol. 2005 Dec 1;162(11):1062-9.

Omodei D, Fontana L. Calorie restriction and prevention of age-associated chronic diseaseFEBS Lett. 2011 Jun 6;585(11):1537-42.

Ruggiero C, Metter EJ, Cherubini A, Maggio M, Sen R, Najjar SS, Windham GB, Ble A, Senin U, Ferrucci L. White blood cell count and mortality in the Baltimore Longitudinal Study of AgingJ Am Coll Cardiol. 2007 May 8;49(18):1841-50.

Walford RL, Mock D, Verdery R, MacCallum T. Calorie restriction in biosphere 2: alterations in physiologic, hematologic, hormonal, and biochemical parameters in humans restricted for a 2-year period. J Gerontol A Biol Sci Med Sci. 2002 Jun;57(6):B211-24.

Weijenberg MP, Feskens EJ, Kromhout D. White blood cell count and the risk of coronary heart disease and all-cause mortality in elderly menArterioscler Thromb Vasc Biol. 1996 Apr;16(4):499-503.