Higher SHBG Slows Aging, Increases Chance to Reach Top 1% Lifespan by 70%?

#1

40% increase in chance to 90th percentile (Top 10%) for either SHBG or Estradiol
70% chance for SHBG to 99th percentile (Top 1%).

This is in females. What could be the mechanism of action? Could it be similar in males? Calorie restriction increases SHBG?

Also: this is a human study… not mice.

Great journal: Cell Medicine

In this comprehensive study, we found that genetically determined later reproductive events, such as older AFB, AFS, and AAM, as well as elevated estradiol and SHBG levels, were causally associated with increased longevity and decelerated biological aging.

Genetically determined per year increase in age at first birth (AFB) (inverse-variance weighted [IVW]-estimated odds ratio [OR], 1.21; 95% confidence interval [CI], 1.12 to 1.30; p = 1.28 × 10−6) and per log-transformed unit increase in estradiol levels (OR, 1.35; 95% CI, 1.29 to 1.41; p = 4.02 × 10−36) were causally associated with higher odds of achieving 90th percentile longevity, both results remaining significant at the phenotype-adjusted Bonferroni threshold (p value < 2.25 × 10−4, Figure 2A). Conversely, genetic liability to pre-eclampsia was strongly associated with lower odds of reaching 90th percentile longevity. Genetically predicted older age at first sexual intercourse (AFS), AAM, and elevated sex hormone-binding globulin (SHBG) levels were suggestively associated with increased odds of achieving 90th percentile longevity, while genetically predicted levels of follicle-stimulating hormone (FSH) had the opposite effect (nominally significant, p < 0.05). However, reproductive behaviors were not significantly associated with 99th percentile longevity. For this extreme aging measure, genetically predicted levels of estradiol** (OR, 1.44; 1.24 to 1.68; p = 1.84 × 10−6) and SHBG (OR, 1.41; 1.01 to 1.98; p = 0.045) maintained positive effects

image
image762×854 136 KB

Genetically predicted SHBG levels remained positively related with higher odds of both the 90th (1.45; 1.10 to 1.92; p = 9.79 × 10−3) (Figure 3A) and 99th (1.72; 1.13 to 2.62; p = 1.11 × 10−2) (Figure 3B) percentile longevity following the respective adjustments.

image
image703×900 183 KB

Among cardiovascular diseases, heart failure mediated the largest proportion of the association between AFB and 90th percentile longevity (28.16%; 95% CI, 12.98%–46.81%), followed by coronary heart disease (CHD), myocardial infarction (MI), stroke, and atrial fibrillation. Alzheimer’s disease (14.81%; 95% CI, 2.98%–27.40%) and chronic obstructive pulmonary disease (COPD) (8.16%; 95% CI, 0.06%–18.88%) were also significant mediators. Ferritin, associated with trace element disorders, accounted for 8.46% of the association. Heart failure also mediated a significant proportion of the association between AFS and longevity (38.06%; 95% CI, 14.50%–67.71%). Other diseases, including atrial fibrillation, type 2 diabetes (T2D), MI, CHD, COPD, and stroke, mediated 8.47%–29.74% of the total effect, with T2D and stroke additionally mediating the association between AFS and DNAm-based biological age acceleration. For AAM, heart failure mediated the largest proportion of its association with 90th percentile longevity, followed by CHD, MI, and COPD. Regarding reproductive hormones, the association between SHBG and 90th/99th percentile longevity was mediated primarily by stroke and Lewy body dementia, accounting for 35.84%–59.86% of the total effects. Lung diseases—such as COPD, lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma—primarily mediated the associations between AFB, AFS, preterm delivery, and DNAm-based biological age acceleration, accounting for 11.88%–44.07% of the total effect. The mediators of the relationships between primary ovarian failure, irregular menses, EVP, post-term delivery, and aging phenotypes were MI, stroke, and T2D

https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(25)00554-3

2 Likes
#2

" Long-term calorie restriction increases SHBG in rodents and men, while lowering free and total testosterone and estradiol and having no effect on DHEA-S, which lacks affinity for SHBG"
@Neo and others thoughts?

#3

I’m on my phone so it’s not convenient for me to read the study atm, but do they provide values? In the posts above, what would be useful is to put some numbers on it, otherwise we don’t know what “low” and “high” means and it’s pretty abstract talk.

For example LabCorp gives (going off memory, but I’m pretty sure this is correct) a reference interval range of 19.3 - 76.4 nmol/L for serum SHBG. Anything outside this range would get flagged by LabCorp, presumably based on some kind of algorithm from a database either clinical or just their population cohort values. So now, in these studies are we talking inside or outside the range for a classification of high/low. What are the concrete values.

1 Like
#4

It should per 1 SD from the 50th percentile, which is the 84th, in linear MR studies. The reference interval range in blood tests usually is 5th to 95th percentile iirc.

So 84th percentile SHBG compared to 50th percentile could increase odds of 99th percentile lifespan for women by 70%, though this is a lifelong effect, mainly via stroke and LBD:

Regarding reproductive hormones, the association between SHBG and 90th/99th percentile longevity was mediated primarily by stroke and Lewy body dementia, accounting for 35.84%–59.86% of the total effects.

Based on another study these are the normal levels and SD:

The mean expression levels of SHBG in male and female healthy volunteers were 29.0±11.6 and 46.4±12.8 nmol/l, respectively.

So around 46 nmol/L vs 59 nmol/L, for women, depending on which dataset you use.

It’s inside the range (though two SD would technically have a 1.72*1.72 effect). There’s a lot of questions about this with such a large effect. It’s barely significant with a wide CI.

1 Like
Predicting Alzheimers & Dementia (and minimizing risk)
#5

SHBG binds to testosterone. In men, you want lower SHBG since testosterone helps insulin resistance, and muscle retention. In women, you want SHBG high so that free testosterone doesn’t cause androgenic symptoms. Low SHBG is also associated with pcos in women. Estrogen increase SHBG in women, so high E2 and high SHBG makes sense.

BTW, sex hormones are is one of the few areas where you don’t have to look at rodent medicine for mechanisms, there is plenty of human literature that can explain it, thankfully.

1 Like
#6

This is an interesting topic…

My Prompt:

What are the percentile curves and related measures for either SHBG in men and women

Gemini Response:

The following overview details the statistical distribution of Sex Hormone-Binding Globulin (SHBG) and its critical clinical implications.

Standard Medical Disclaimer: This information is for educational purposes only and does not constitute medical advice. Reference ranges vary by laboratory assay.

1. SHBG Reference Intervals & Percentiles

SHBG levels are not static; they exhibit distinct sexual dimorphism and age-related trajectories.

Men: The Age-Related Climb

In men, SHBG increases with age. This is a primary driver of the age-related decline in free testosterone, even if total testosterone remains relatively stable.

  • Trajectory: Rises ~1.0% per year after age 30.
  • Mechanism: Lower insulin/IGF-1 levels in healthy aging (or varying liver function) reduce the inhibition of SHBG synthesis, allowing levels to drift up.

Standard Clinical Ranges (Mayo Clinic / EMAS Data):

Age Group 2.5th Percentile 50th Percentile (Median) 97.5th Percentile
Young Adult (20–49) ~16 nmol/L ~35 nmol/L ~57 nmol/L
Older Adult (>50) ~20 nmol/L ~45 nmol/L ~82 nmol/L
  • Clinical Red Flag: Levels < 15 nmol/L are strongly correlated with insulin resistance, obesity, and NAFLD (Non-Alcoholic Fatty Liver Disease).
  • Frailty Marker: Levels > 80 nmol/L in elderly men are associated with malnutrition, frailty, and increased mortality.

Key Reference:
Association of age and insulin resistance with sex hormone-binding globulin levels in healthy men (European Male Ageing Study)

Women: The U-Shaped Curve

Women have significantly higher SHBG than men (up to 2x). The trajectory is U-shaped: levels are high in young adulthood, decline through mid-life (often tracking with weight gain/insulin resistance), and rise again after age 60.

Standard Clinical Ranges:

Status / Age Lower Limit (5th %) Median (50th %) Upper Limit (95th %)
Premenopausal 18 nmol/L ~60 nmol/L 144 nmol/L
Postmenopausal 18 nmol/L ~58 nmol/L 125 nmol/L
  • The “Pill” Effect: Oral contraceptives containing ethinyl estradiol can skyrocket SHBG to 200–400 nmol/L. This state can persist for months or years after cessation, leading to a “functional” testosterone deficiency despite normal total T production.
  • Pregnancy: Levels naturally surge (often >400 nmol/L) to buffer high circulating hormones.

Key Reference:
Sex hormone binding globulin levels across the adult lifespan in women (Maggio et al., 2008)

2. Critical Measures & Calculations

Measuring SHBG alone is clinically insufficient. It is a variable in an equation, not the final answer.

A. Free Androgen Index (FAI)

A crude ratio used primarily in women to detect androgen excess (PCOS).

  • Formula: (Total Testosterone / SHBG) x 100
  • Women’s Target: < 5.0 (Higher suggests PCOS/Hyperandrogenism).
  • Men’s Target: 30–150 (Lower suggests Hypogonadism).

B. Calculated Free Testosterone (cFT)

The Vermeulen Equation is the gold standard for estimation. It accounts for the differing binding affinities of SHBG (tight) and Albumin (loose).

Inputs Required:

  1. Total Testosterone
  2. SHBG
  3. Albumin (Default: 4.3 g/dL)

Why it matters: A man with “High” Total Testosterone (900 ng/dL) but High SHBG (80 nmol/L) may have the same bioavailable testosterone as a man with “Low” Total T (400 ng/dL) and Low SHBG (20 nmol/L).

3. The “Tell It Like It Is” Analysis

Hormone data is often misinterpreted. Here is the objective reality regarding SHBG and longevity.

1. The “Goldilocks” Mortality Curve
Mortality risk is U-shaped.

  • Low SHBG (< 20 nmol/L): You are likely insulin resistant. The liver stops producing SHBG when flooded with insulin. This is a surrogate marker for Type 2 Diabetes and cardiovascular risk.

  • Reference: Sex hormone-binding globulin and the risk of type 2 diabetes (Ding et al., 2009)

  • High SHBG (> 70-80 nmol/L in men): While often praised as “clean” living, in the elderly, very high SHBG correlates with higher all-cause mortality. This is likely because it reflects low IGF-1 (growth factor) and catabolic wasting, not because the protein itself is toxic.

2. The Thyroid Connection
SHBG is a sensitive marker for thyroid function.

  • High SHBG can indicate Hyperthyroidism (Thyroid hormone stimulates SHBG production).
  • Low SHBG can indicate Hypothyroidism.
  • Practical Note: If your SHBG is inexplicably high/low, check your T3/T4/TSH before adjusting testosterone protocols.

3. The “Free T” Trap
Many clinics treat the number, not the patient. “Crushing” SHBG (using Boron, Stinging Nettle, or Danazol) to free up testosterone is a common biohacker strategy. However, SHBG has its own receptor sites on cell membranes (cAMP signaling). Excessive suppression of SHBG to boost Free T may paradoxically reduce the transport of hormones into specific tissues that rely on the SHBG-complex for entry.

#7

None of these links point to the articles.

The AI should specify whether this is on women or men. For men, that seems doubtful.

#8

Updated the post after getting Gemini to check and verify the links. I think they are good now.

#9

It links to here: Virus-induced autoimmune diabetes in the LEW.1WR1 rat requires Iddm14 and a genetic locus proximal to the major histocompatibility complex - PubMed

1 Like
#10

Fixed:

https://www.nejm.org/doi/full/10.1056/NEJMoa0804381

2 Likes
#11

Wow. Higher SHBG levels nukes Type 2 Diabetes Risk.

In mendelian randomization analyses, the predicted odds ratio of type 2 diabetes per standard-deviation increase in the plasma level of sex hormone–binding globulin was 0.28 (95% CI, 0.13 to 0.58) among women and 0.29 (95% CI, 0.15 to 0.58) among men, a finding that suggests that sex hormone–binding globulin may have a causal role in the risk of type 2 diabetes.

@qBx123Yk both men and women according to this study.

2 Likes
DIY Mendelian Randomization -- mrbase.org
#12

Cross-sectional analyses at baseline revealed that higher levels of sex hormone–binding globulin were associated with lower BMI, a lower likelihood of having a history of hypertension, and more favorable lipid-profile and CRP levels

Sounds like anti-aging

#13

Excellent, thanks. The paper makes it clearer

2 Likes
#14

This has made me reconsider my anti-sarcopenia as MK-2866 drastically suppresses SHBG as it’s processed by the liver. Going to do a Tamoxifen PCT exit.

#15

I saw this short from Michael Lustgarten @ConquerAging https://www.youtube.com/shorts/9In3aSgdEc8

I have not done a transcript/summary because it is short.

I have had a high SHBG for some time outside the normal range. This may be melatonin linked.

#16

Here’s the proposed mechanism for SHBG and type 2 diabetes:

Our prospective findings for plasma levels of sex hormone–binding globulin levels and risk of type 2 diabetes are consistent with results from previous cross-sectional studies of diabetes.6,8 Sex hormone–binding globulin may play an important role in the pathogenesis of type 2 diabetes, by modulating the biologic effects of sex hormones (testosterone and estrogen) on peripheral tissues (i.e., liver, muscle, and fat). Studies suggest that sex hormones bound to sex hormone–binding globulin may also be biologically active, amplifying their signaling, endocytosis, or overall biologic actions.1–3 For example, sex hormone–binding globulin has been shown to have direct cellular antagonistic properties against estrogen4,32; interaction of sex hormone–binding globulin with the cellular estrogen receptor can trigger a biologic antiestrogen response,4 a form of mediation beyond simple hormone sequestration. Our results may provide a potential explanation of the intriguing divergent effects on the risk of diabetes, observed in two randomized trials, of transdermal estradiol (which elevates plasma glucose levels) and oral estrogen (which lowers glucose levels).33–35 In direct comparisons, transdermal estradiol does not affect sex hormone–binding globulin levels, whereas oral-estrogen therapy favorably increases levels of sex hormone–binding globulin.36–38