Why More Fat Isn’t Always the Answer: Rethinking Ketogenic Strategies in Midlife Women

The ketogenic diet has gained traction for its effects on mitochondrial biogenesis, neuroprotection, and metabolic health. But in midlife women - especially those experiencing perimenopause or menopause, the picture is rarely so straightforward.

Hormonal decline, circadian misalignment, and impaired fat partitioning create a terrain where the body’s ability to burn fat becomes compromised, even as fat intake increases. In these cases, high-fat, low-carb protocols may inadvertently drive metabolic dysfunction via lipotoxicity -the pathological accumulation of fatty acids in non-adipose tissues such as liver, pancreas, and muscle (Unger et al., 2010).

Oestrogen plays a key role in maintaining mitochondrial efficiency, fat oxidation, and insulin sensitivity (Yao et al., 2010). As levels fall, the ability to store and utilise fat safely declines. Adiponectin, a hormone that enhances lipid oxidation is also suppressed during this transition, further impairing metabolic flexibility (Clegg et al., 2006).

Many midlife clients report paradoxical outcomes on ketogenic or carnivore diets: increased fatigue, rising fasting insulin, disrupted lipid panels, or unexplained weight gain - despite perfect adherence and low carbohydrate intake.

From a mechanistic standpoint, excess dietary fat - especially saturated fat can exceed mitochondrial oxidative capacity, triggering reactive oxygen species (ROS), ceramide accumulation, and inflammatory signalling (Listenberger et al., 2003). This is compounded by low bile output, reduced thyroid function, and gallbladder sluggishness - common features in this demographic.

And while ketones such as beta-hydroxybutyrate (BHB) can mimic some benefits of short-chain fatty acids (e.g., HDAC inhibition, anti-inflammatory effects), they are not equivalent to butyrate in the gut. Butyrate is locally produced and utilised in the colon, maintaining tight junction integrity, pH balance, and microbial diversity, roles BHB cannot fulfil (Canani et al., 2011).

We must also consider the light environment. Mitochondria are circadian-bound organelles, deeply responsive to light cues. Without adequate exposure to morning UVA, infrared, and full-spectrum daylight, mitochondrial signalling is impaired, regardless of dietary inputs (de Goede et al., 2018).

The takeaway?

Midlife metabolism isn’t broken, it’s context-dependent. High-fat diets may still have therapeutic value, but only when supported by:

• Adequate bile flow and fat digestion (e.g., bitters, choline, ox bile)

• Circadian realignment (light, sleep, feeding windows)

• Hormonal recalibration (especially oestrogen and thyroid)

• Mitochondrial support (CoQ10, PQQ, magnesium, carnitine)

• Judicious reintroduction of carbohydrates to restore flexibility

Conclusion:

While ketogenic diets may offer mitochondrial benefits in select cases, their application in midlife women requires greater clinical nuance. Hormonal shifts, reduced metabolic flexibility, and underlying lipotoxicity mean that high-fat approaches can sometimes do more harm than good. Personalised assessment, rather than macronutrient ideology, should guide metabolic interventions - especially in the context of ageing, inflammation, and hormonal decline.

References

• Unger RH, et al. Cell Metab. 2010

• Yao J, et al. Biochim Biophys Acta. 2010

• Clegg DJ, et al. Diabetes. 2006

• Listenberger LL, et al. PNAS. 2003

• Canani RB, et al. Curr Opin Gastroenterol. 2011

• de Goede P, et al. Front Physiol. 2018