Ketogenic diet can accelerate aging
Research shows how the ketogenic diet can induce cellular senescence, increasing the number of aged and damaged cells.
The ketogenic diet is a medical diet that can improve certain conditions and, for some people, promote weight loss. But it should be managed on an individual basis and applied intermittently with breaks.
The ketogenic diet, high in fat and low in carbohydrates causes the body to break down fat into molecules called ketones. These become the main source of energy for many cells in the body. A ketogenic diet has been recognized for years to be helpful in some forms of treatment resistant epilepsy. (This was assumed to be due to a neuronal stabilizing effect, but more recent research suggests the mechanism may be changes in the gut microbiome.) The drop in insulin triggered by the ketogenic diet can also be beneficial for a number of conditions. But research just published in Science Advances (AAAS) shows that the ketogenic diet can also backfire if administered without sufficient care.
The authors note:
“Multiple publications provide evidence that the primary ketone produced in ketogenesis, β-hydroxybutyrate (β-HB), may be anti-inflammatory (14, 66), suggesting that this could play a mechanistic role in the beneficial effects of KDs (8, 10). In contrast, others have shown KDs are pro-inflammatory and lead to organ disorders, including cardiac fibrosis and kidney damage (15–19, 67)…””
Keto diet effects are complex and can cause cellular senescence
This study adds to the evidence that a prolonged ketogenic diet can induce cellular senescence, a form of aging in which the cell is in a state of irreversible growth arrest but can still promote chronic inflammation throughout the body. The authors of this study used enzyme-linked immunosorbent assay (ELISA) to measure biomarkers of the SASP including tumor necrosis factor–α (TNFα), interleukin-1β (IL-1β), and IL-6, important pro-inflammatory signaling agents.
“Senescent cells can adversely affect adjacent cells and the tissue microenvironment by secreting pro-inflammatory cytokines (37)…While these cytokines are produced by various cells and have pleiotropic effects, they are frequently produced by senescent cells and have been shown to be pro-inflammatory (61). All were significantly increased in mouse sera following a 21-day KD (Fig. 6A). We also found similar up-regulation of SASP [senescence-associated secretory phenotype] biomarkers in the heart, kidney, and liver tissue samples collected after 7- and 21-day KDs (fig. S6, D to F).”
These effects are independent of age:
“All mice, regardless of age, showed a significant increase in p53, p21, and SA-β-gal [promoters of senescence] in both heart and kidney tissue on KD, compared to age-matched controls (Fig. 7, A to F), and comparable to mice starting the 21-day KD at 6 weeks of age.”
Interestingly, they also demonstrated that the effects were independent of the form of fats used:
“These data support that cellular senescence can be induced by sustained KD, independent of age or lipid composition, and is not an artifact of reduced dietary protein.”
Translation to humans subjects
(B and C) TNFα, IL-1β, and IL-6 measured by ELISA in plasma collected from male (B) (n = 5, except 4 at baseline) and female (C) (n = 11) patients at baseline and after 3 and 6 months on a clinical KD trial. P values were calculated by one-way ANOVA followed by Dunnett’s multiple comparisons test.
These findings were replicated in human subjects:
“We next examined the relevance of these observations to humans by analyzing plasma samples from a published clinical trial by our institution (62) in which patients of varying age, sex, and health condition were assigned to a KD, with fasting blood samples collected at the start of the trial (baseline) and after 3 and 6 months. Patients in this trial were monitored to confirm that they were in ketosis (62). In both male (Fig. 6B) and female patients (Fig. 6C), samples obtained after 6 months KD showed a significant increase in both TNFα and IL-1β compared to baseline. We saw a similar trend in IL-6, with a significant increase in female patients after 6 months KD (Fig. 6C). In contrast, there was no change or only a modest increase in these pro-inflammatory biomarkers after 3 months on KD. These data support that a long-term KD can induce SASP in humans of varied age, sex, and health, similar to what we observed in mice on a 21-day KD.
It appears to be the lipids, not the ketones, that are responsible.
“Last, we used a NIH 3T3 cell culture model that suggests it may be the increased lipids or lipoproteins, rather than the increase in ketone levels, that play a role in p53-induced cellular senescence on a KD (fig. S8A).”
Ketogenic diet benefit or harm is influenced by multiple factors
“It is increasingly evident that the effects of a KD are complex, and the health-related outcomes of its use likely depend on multiple factors (65). Some of the conflicting reports appear to revolve around whether a KD is pro- or anti-inflammatory. Multiple publications provide evidence that the primary ketone produced in ketogenesis, β-hydroxybutyrate (β-HB), may be anti-inflammatory (14, 66), suggesting that this could play a mechanistic role in the beneficial effects of KDs (8, 10). In contrast, others have shown KDs are pro-inflammatory and lead to organ disorders, including cardiac fibrosis and kidney damage (15–19, 67) perhaps due to the increase in lipids or lipoproteins, which have been shown previously to be detrimental (68). An important study suggests that diet duration may be key in determining this outcome by showing a short-term KD improved murine metabolism through activation of tissue-specific resident immune cells, while a long-term continuous KD induced systemic inflammation, obesity, and glucose intolerance (9).”
Duration of the ketogenic diet may be the key
The good news is that the ketogenic diet-induced cellular senescence is time-dependent and reversible, and that an intermittent ketogenic diet (IKD) does not induce cellular senescence. Moreover:
“An important study suggests that diet duration may be key in determining this outcome by showing a short-term KD improved murine metabolism through activation of tissue-specific resident immune cells, while a long-term continuous KD induced systemic inflammation, obesity, and glucose intolerance (9).”
This has great practical significance:
“Several recent studies have reported benefits from various IKD protocols. An alternate-day KD improved cardiac function in a murine model of heart failure (64), while an alternate-week KD reduced midlife mortality, age-related memory loss, and other health issues in male mice (10). To evaluate whether an IKD would avoid p53 activation and cellular senescence, we placed mice on alternating 4-day KD and 7-day standard diet for three cycles (IKD), a 31-day KD (positive control), or a standard diet (negative control). In contrast to the sustained KD, the IKD did not increase p53 or cellular senescence (Fig. 8, G and H, and fig. S8, D and E), nor did IKD increase SASP biomarkers in the tissues (fig. S8, F and G). These data potentially have important clinical application because they suggest that IKD may have fewer side effects than sustained KD while still potentially having a positive influence on health-related end points (10, 64).”
Summary of clinical implications
“Because we observed that these changes in key organs such as the heart and kidneys, where the accumulation of senescent cells can contribute to systemic inflammation and toxicity (3, 18, 19), we believe that they have important clinical implications. In this regard, two publications showed a long-term KD promoted cardiac fibrosis and dysregulated mitochondrial function, due to chronic inflammation (18, 67)… Furthermore, it was recently published that KD-fed mice develop hepatic injury, steatosis, inflammation, glucose intolerance, and insulin resistance (22). In light of all these data and that our mice on a KD also showed reduced glucose tolerance, it could be hypothesized that metabolic dysfunction on a KD may lead to increased cellular senescence in specific conditions. There is an increasing consensus that the buildup of senescent cells, whether by increased induction or impaired clearance, contributes to age-related diseases and even aging itself (28, 29, 60, 69). Our analyses of SASP pro-inflammatory cytokines in patients suggest that cellular senescence may also be associated with sustained KD in humans.”
Intermittent application of the ketogenic diet is a crucial point:
“Our study showed that an IKD can prevent the accumulation of senescent cells induced by sustained KD. This observation builds on that of others (10, 64), suggesting that an IKD may be more beneficial than a long-term continuous KD, perhaps by avoiding eventual pro-inflammatory activation (9). These data may be of clinical relevance because it could be surmised that the accumulation of senescent cells in children on a continuous KD, as used for refractor seizures, could play a role in the documented long-term side effects (71–73)… Our results showed a significant reduction in p53, p21, and SA-β-gal after returning to a normal diet for 1-week, suggesting an IKD may be a potential alternative clinical intervention to a continuous KD.”
An alternate week or alternate day application may be better and easier.
“An IKD could be especially relevant in the clinic, as this type of KD may be easier for patients to adhere to and could potentially offer many of the benefits of weight loss and improved health parameters without the risk of cellular senescence from sustained KD. In this regard, both an alternate-day and an alternate-week IKD have been reported to improve health parameters over a continuous KD in different murine models (10, 64), while a third study using a 3-day/week IKD reported attenuated improvements relative to continuous KD (74). Further research is clearly needed to determine whether and for what conditions an IKD could be beneficial in humans, as well as the optimum regimen.”
The authors conclude with a sound recommendation:
“The results of our in vivo murine experiments in this study, as well as those from other laboratories, reinforce that the effects of KD are complex, with both potential benefits and side effects likely due to multiple factors, including the timing, composition of the diet and the genetics, endocrine factors, and health conditions of the individual. As such, it is proposed that the use of a KD should be considered within the overall scope of personalized medicine, where the variables for each patient are taken into consideration to determine who will, and who will not, benefit from this dietary intervention as well as the specific regimen to follow.”
