Critical Analysis

Cellular reprogramming includes "pluripotent reprogramming," "partial reprogramming," and "direct reprogramming." In pluripotent reprogramming, somatic cells are completely reverted to a pluripotent state; in partial reprogramming, these cells may be rejuvenated but do not lose their cellular identity; and in direct reprogramming (transdifferentiation), somatic cells are directly converted into another type of differentiated cell.

The iPS cells generated by pluripotent reprogramming, according to the “Telomere and rDNA co-regulation model for cell senescence,” have been found to have significantly increased telomere length and rDNA array length compared to senescent somatic cells, indicating that the cellular age is reversed to 0 years. However, iPS cells or adult cells differentiated from iPS cells can also be subject to immune rejection. For example, on May 13, 2011, Nature reported that American scientists transplanted mouse iPS cells or adult cells differentiated from iPS cells into mice from which the cells were derived. It was originally thought that there would be no rejection due to the identical genetic background, but the mice rapidly rejected the transplanted cells [1]. On August 11, 2022, a paper published in Nature Genetics confirmed that nearly three-quarters of iPS cell lines have severely damaged DNA. Moreover, allogeneic iPS cells with the same homozygous human leukocyte antigen (HLA) haplotype as the patient can still cause immune rejection [2], indicating that even with the same HLA, allogeneic stem cells will still be rejected. In 2024, Deng Hongkui and others published a paper in Cell on the transplantation of islets derived from chemically induced pluripotent stem cells (CiPSCs) for the treatment of type 1 diabetes. The use of immunosuppressive agents indicates that small molecule reprogramming can also be rejected [3]. The original text is as follows: Before CiPSC-islets transplantation, the patient was maintained on immunosuppressive therapy with tacrolimus (2-2.5 mg/day), mycophenolate mofetil (1 g/day) and methylprednisolone tablets (8 mg/day) due to liver transplantation. For CiPSC-islets transplantation, Basiliximab (20 mg) was used for induction therapy on day 0 and day 4. Etanercept was administrated intravenously on day 0 (50 mg) and subcutaneously on day 3, day 7 and day 10 (25 mg) to alleviate inflammatory reactions. For maintenance therapy, the previously described immunosuppressive maintenance regimen for liver transplantation was continued. Cefazolin Sodium was administered for infection prophylaxis during the perioperative period.

Partial reprogramming is also not viable because it has been found that the telomere length does not increase or even slightly decreases in partial reprogramming [4], and it is estimated that the length of the rDNA array does not increase either. After the cessation of Yamanaka factor expression, the epigenetic age quickly reverts to the previous state, and aging symptoms accumulate rapidly. Multiple cycles of treatment only extended the lifespan of progeroid mice by 30%, but failed to extend the lifespan of wild-type mice, indicating that partial reprogramming did not reverse the underlying mechanisms of aging. If in vivo reprogramming is excessive, it can cause mouse death or the formation of iPS cells and fatal teratomas derived from iPS cells. Partial reprogramming uses doxycycline, which is mentioned below to significantly extend the lifespan of Caenorhabditis elegans and mice. The earliest in vivo partial reprogramming experiments were conducted in 2016, and to date, they have not extended the lifespan of normally aging mice. In 2016, Cell reported that cyclic transient expression of the four Yamanaka factors—Oct4, Sox2, Klf4, and c-Myc (abbreviated as OSKM)—in mice significantly extended the lifespan of progeroid mice, but did not extend the lifespan when OSKM was induced in normally aging mice (12 months old) [5]. Altos Labs, founded with $3 billion in investment from the world's richest man Jeff Bezos and Yuri Milner, reported in September 2024 that partial reprogramming only increased the median lifespan of wild-type mice by 12%, which is not as effective as small molecule anti-aging drugs. It can be said that the path of partial reprogramming has been declared a failure [6].

Direct reprogramming has not been found to reverse the aging phenotype [7].

In 2011, a group of American scientists [1] administered drugs to elderly mice (not progeria model mice) and found that they could eliminate senescent cells from many tissues in the body, making the mice younger and stronger: their muscles developed again, their subcutaneous fat thickened, and their cataracts healed, but their lifespans did not increase. I believe that the reason why eliminating senescent cells does not extend lifespan is that eliminating senescent cells may activate adult stem cells to divide to fill the gaps, and cell division can lead to telomere shortening. There are also reports that excessive elimination of senescent cells in the lungs can lead to stem cell depletion and pulmonary fibrosis. A paper titled "Sexual dimorphic responses of C57BL/6 mice to Fisetin or Dasatinib and Quercetin cocktail oral treatment" in GeroScience found that female mice that took dasatinib and quercetin to eliminate senescent cells since youth had accelerated aging [2]; a research paper in Aging in February 2024 used dasatinib and quercetin to eliminate human senescent cells and observed a significant increase in epigenetic age and a significant shortening of telomere length [3]; ABT-263 treatment to eliminate senescent cells accelerated ovarian aging in elderly female mice [4].

Unity Biotechnology's stock price has recently plummeted and the company has been deserted. The reason is that Unity released Phase II clinical data showing that the precise removal of senescent cells in the joints through the drug UBX0101 did not show any statistically significant difference compared with placebo in treating knee osteoarthritis pain [5].

Replication within adipocytes can produce multinucleated cells, leading to replicative senescence. A Nature review article titled “Mechanisms and consequences of endothelial cell senescence” states that the elimination of cardiac senescent cells can lead to the expression of aging markers and the appearance of multinucleated cardiomyocytes, as well as cardiomyocyte hypertrophy [6], which are manifestations of cell replicative senescence. In other words, the elimination of cardiac senescent cells will accelerate the aging of the heart.

It is generally believed that senescent cells accelerate the aging of young cells. However, in 1958, Hayflick and Moorhead mixed male fibroblasts that had divided 40 times and normal female fibroblasts that had divided 10 times, and used cells cultured alone as a control. When the cells cultured alone stopped dividing, the mixed culture cells were examined and found that only female fibroblasts remained. This experiment shows that the cessation of cell division is determined by factors within the cells themselves [7]. In addition, mice that eliminated senescent cells failed to extend their maximum lifespan, indicating that senescent cells do not accelerate the aging of young cells. Moreover, mice that continuously eliminated senescent cells for a long time will age faster, indicating that senescent cells actually inhibit the division of young cells, play a throttling role, and allow young cells to slowly use up the constant number of divisions. The actual role of senescent cells is not to accelerate aging, but to delay aging. The fact that telomeres in children or young people shorten faster than those in middle-aged and elderly people also shows that senescent cells or inflammatory or aging body fluids caused by aging can actually delay aging.

This may be because while activating telomerase, it also activates a mechanism that accelerates telomere shortening. This is because small molecule telomerase activation positively correlates with the expression of the telomere-binding protein TRF2, which inhibits telomere extension. Cancer cells have very high telomerase activity, yet most have very short telomeres. This is primarily due to the positive correlation between telomerase and TRF2 expression, suggesting that small molecule telomerase activators may shorten telomeres.

TA-65 failed to extend the lifespan of mice and even slightly shortened it [1]. In 2014, Nature reported that TA-65, the first anti-aging drug that activates telomerase, was accused of commercial fraud. The small molecule telomerase activator TAC also failed to extend the lifespan of mice. This may be because the telomeres did not significantly extend, which is a common feature of small molecules [2]. How can cancer cells achieve immortality when half have p53 mutations and the other half do not? One of the reasons is that TRF2 can bind to P53. Therefore, when cancer cells overexpress TRF2, it will reduce P53 levels, causing the cancer cells to divide continuously.

In 1972, researchers fed mice a diet containing the antioxidant vitamin E. One year later, they found that lipofuscin levels were indeed lower, but the mice's mortality rate did not decrease, indicating that the oxygen free radical theory of aging is wrong.

Methylene blue (MB) is a strong antioxidant with a significant ability to cross cell membranes and is distributed in different subcellular compartments, such as lysosomes and mitochondria, but it did not extend the average lifespan of mice [1].

Lysosomal autophagy can clear various waste proteins from cells, but it does not extend lifespan. In fact, increased autophagy in the nematode brain or intestine can shorten lifespan. This suggests that the cause of aging is not waste accumulation. Experiments in mice have found that ovarian aging is associated with increased autophagy and apoptosis in granulosa cells, and this can be reversed by estrogen receptor inhibitors [1].

Geranylgeranylacetone（GGA） has an inducing effect on the expression of heat shock proteins in mammalian tissues, ensuring that proteins can be folded correctly. However, tests by the most authoritative National Institute on Aging in the United States have shown that GGA cannot prolong the lifespan of mice [1], indicating that the loss of protein homeostasis is not the cause of aging, but a result of aging [2].

For example, rapamycin has a life-extending effect, but it has significant side effects. This is because many cells in the blood, oral cavity, and intestines need to be rapidly renewed. Inhibiting cell division can affect tissue renewal and cause significant side effects, such as immunosuppression. In 20-month-old mice, rapamycin was given to extend the median lifespan of male mice by only 9% and that of female mice by 14% [1].

Rapamycin, a commonly used immunosuppressant in organ transplants, can cause tumors. One study reported that lung transplants led to cancer cell transmission due to the use of immunosuppressants. Some people abroad reported rapidly enlarging facial melanocytic nevi and developing basal cell carcinoma after taking rapamycin.

On June 4, 2024, the American Society of Aging in Wisconsin published a report on a decade-long life-extending study of rapamycin in 60 marmosets, finding that the median lifespan increased by 15%. The study used a daily dose of 1 mg/kg, a relatively high dose used only in experimental animals, as the marmosets were living in a pathogen-free environment and are not prone to cancer. Humans, however, are exposed to various pathogens and are susceptible to cancer, so high doses are not recommended. Therefore, the life-extending effect in humans may be minimal, and may even shorten lifespan.

Klotho protein acts as a circulating hormone, binding to cell surface receptors and inhibiting the intracellular signaling of insulin and insulin-like growth factor 1 (IGF1). This lifespan extension is essentially achieved by reducing metabolic rate, and therefore, like rapamycin, it also inhibits cell replication and immune function. For example, some studies have shown that α-Klotho has a lifespan extension effect on male mice, but not on females [2]. This may be because females have a lower metabolic rate than males, and further reducing the metabolic rate is harmful. It has also been found that excessive Klotho increases the risk of cancer in cancer survivors [3].

Researchers from the University of Salford in the UK found that antibiotics can inhibit mitochondrial ATP production. When young Caenorhabditis elegans were treated with doxycycline at concentrations of 13 μM (6 μg/ml) and 130 μM (60 μg/ml), the lifespan of the treated groups was significantly extended by 72.8% and 63.64%, respectively, compared with the control group. Thirteen days after doxycycline treatment, the content of the aging pigment lipofuscin in the Caenorhabditis elegans treated with 13 μM doxycycline decreased by about 50%, while that of the 130 μM treatment decreased by about 90%. Treatment with the antioxidant vitamin C, however, resulted in a significant increase in ATP production by 2.5 times or more, which not only failed to extend lifespan but also accelerated aging and shortened lifespan. Eight days after treatment, the lipofuscin content in the worms increased by about 18% [1]. Recently, researchers including Liu Baohua and Wang Ming from the School of Basic Medicine, School of Medicine, Shenzhen University, published a research paper titled "Doxycycline decelerates aging in progeria mice" in the journal "Aging Cell". The study showed that doxycycline can slow down aging and prolong lifespan in a mouse model of progeria [2].

There are no reports of pyrroloquinoline quinone (PQQ) extending mouse lifespan. Coenzyme Q10 (ubiquinone 10) has also not been reported to extend mouse lifespan. Because PPQ and Coenzyme Q10 enhance mitochondrial function and have an overdraft effect, they are likely to shorten mouse lifespan.

Gene mutations are considered to be the cause of aging. Ionizing radiation can cause DNA damage and gene mutations. However, fruit flies and mice actually extend their lifespan when exposed to ionizing radiation in doses less than lethal.

Promoting cell division may accelerate telomere shortening and shorten lifespan. For example, growth hormone can shorten the lifespan of mice. The regeneration process will activate the Wnt signaling pathway. In 2011, Rabbani et al. found that overactivation of the canonical Wnt signaling pathway in transgenic mice can produce white hair [1]. Recently, Liu Guanghui et al. found that uridine has a significant effect on promoting tissue repair and regeneration in mammals [2]. Uridine is the raw material for synthesizing uracil in RNA. Therefore, I believe that long-term use of uridine will accelerate aging because uridine can promote RNA and protein synthesis, which will accelerate the reduction of rDNA and telomeres. On the contrary, someone in the former Soviet Union used olive mycin, which can inhibit the transcription of DNA into RNA and thus inhibit protein synthesis, to feed fruit flies. As a result, the lifespan of fruit flies was extended by 20-30%. Actinomycin D, which can inhibit protein synthesis, also has the same effect [3].

Tissue-specific adult stem cells reside in every organ and tissue. Cells that perform physiological functions in organs and tissues often die due to aging, gene mutations, and viral infections, and are then replaced by stem cells in the tissues. Since adult stem cells themselves can also age, in theory, young adult stem cells can significantly prolong lifespan.

However, the stem cell anti-aging therapy currently used by many people usually uses allogeneic mesenchymal stem cells, which are fundamentally unable to replace the specific adult stem cells in the tissue, and allogeneic stem cells will be quickly eliminated by the immune system [1]. Stem cells taken from the body will produce "replicative aging" after expansion, and the infusion of stem cells older than the body will not have the effect of prolonging life, and may even accelerate aging. For example, in a research report published in the international journal EBioMedicine, researchers from the Lineberger Comprehensive Cancer Center at North Carolina State University found that stem cell transplantation will accelerate certain aspects of aging in the body. They found that after blood cancer patients received hematopoietic stem cell transplantation, T cells and bone marrow stem cells aged 30 years in advance [2]. In addition, the injection of allogeneic stem cells will be quickly eliminated by the immune system and have no anti-aging effect. In addition, the human body has dozens of adult stem cells, and it is currently impossible to inject dozens of stem cells in accordance with the corresponding types.

Stem cell lysate is equivalent to the exosomes of stem cells. A total of 92 rats were randomly divided into a treatment group and a control group in a 3-year lifelong experiment. Mesenchymal stem cell lysate was administered 3 times a week, 11 times every other month, starting from 12 months of age until natural death. In confirming the previous studies on the effects of long-term MSC lysate treatment on fat loss and insulin resistance, it was found that compared with the control group, the average lifespan of MSC lysate rats was shortened, the inactivity time was prolonged, the bone loss increased, and the lean body mass was relatively increased. The researchers concluded: Our data show that MSC lysate treatment will produce the same cachexia-like symptoms as those in tumor patients, leading to a shortened lifespan [3].

That simply doesn't work, because cellular aging is a process of continuous differentiation in gene expression patterns. That is, as we age, our cells change their gene expression patterns, shifting from those that favor youth to those that favor aging. However, the root cause of aging isn't genetic, as the genomes of young and old cells are identical. Genes simply influence the rate of aging. Somatic cell cloning of animals has also demonstrated that the genes of young and old animals are identical.

Longevity genes extend lifespan by slowing the rate of shortening of telomere and rDNA. For example, genes that repair DNA damage can slow down the replicative aging of cells in two ways. The ways in which DNA damage leads to cell aging include: (1) Telomere and rDNA are multi-copy tandem repeat DNAs, which are inherently very unstable. In the presence of DNA damaging agents, they are more likely to lose their copy number, thereby accelerating replicative aging. Moreover, rapid shortening of telomeres has also been found in progeria; (2) Cells with DNA damage are prone to apoptosis or are eliminated by the immune system, which stimulates the division of surrounding cells to fill the gap, thereby accelerating the replicative aging of cells.

It doesn't work, as it hasn't been shown to extend mouse lifespan. In 1958, Hayflick and Moorhead mixed male fibroblasts that had divided 40 times with normal female fibroblasts that had divided 10 times, and also used cells cultured alone as a control. When the cells in the individual cultures stopped dividing, they examined the mixed cultures and found only female fibroblasts remained. This experiment suggests that cell division cessation is determined by factors within the cells themselves. This experiment suggests that young blood has no life-extending effect. Furthermore, blood transfusions can reduce the activity of the host's macrophages and natural killer cells, increasing tumor recurrence rates. Plasma transfusions have the most significant effect on suppressing the immune system, followed by white blood cell transfusions. The typical lifespan of mice is 2.5 years (30 months). A 2014 research paper compared the repeated injections of young plasma into old mice with a control group that received saline. The median lifespan of the control group was 27 months, while that of the plasma-treated group was 26.4 months. Not only did it not extend lifespan, it actually shortened it slightly.

Age-related changes in DNA methylation are not the cause of cellular aging, but rather the result of cellular aging. Histones are very unstable, and methylation or acetylation of histones is even less likely to be the cause of cellular aging. At most, they can only affect the rate of aging. Furthermore, some organisms have little or no methylated DNA, yet their cells still age. This also does not support the theory that epigenetics is the cause of cellular aging. For example, the DNA of the grain pest Tribolium castaneum is not methylated [1]; nematodes such as Caenorhabditis elegans also do not have methylated DNA. In a paper published on October 18, 2012 in the internationally renowned journal Genome Biology, researchers from Jilin University and BGI collaborated to study DNA methylation in 11 species of nematodes and found that Trichinella spiralis was the only species with methylation [2]. DNA methylation can only be detected in Drosophila in the early stages of embryonic development, and the level is extremely low, with the level of cytosine methylation in the entire genome less than 1%. In other developmental stages, the methylation level is much lower, for example, the level of cytosine methylation in the adult stage is only about 1/1300 [3], which is difficult to detect using conventional methods [4].

It doesn't work because calorie restriction only extends lifespan in adolescent mice, while calorie restriction in adult mice has little effect. In other words, middle-aged and elderly people don't eat much anyway, so dieting has little impact on lifespan. It's even more unworkable in humans because restricting calorie intake in adolescents would affect puberty and height growth.

An article titled "Translational Regulation of Non-autonomous Mitochondrial Stress Response Promotes Longevity" states that two signaling pathways in the nematode Caenorhabditis elegans are associated with aging: one is the insulin signaling pathway, and the other is the TOR signaling pathway. Previous studies have found that these two pathways are related to the lifespan of nematodes, extending their lifespan by approximately 100% and 30%, respectively. However, altering these two pathways simultaneously does not result in a lifespan extension effect of one plus one equals two, but rather five! This can extend the lifespan of nematodes by 500% [1].

The life-extending mechanism of these two pathways is mainly through reducing energy consumption and inhibiting cell replication and division. Since nematodes are cold-blooded animals and adult nematode cells almost no longer replicate and divide, changing these two pathways at the same time will have no problem extending the lifespan of nematodes. However, mammals are warm-blooded animals and many tissue cells need to be quickly renewed. Therefore, energy consumption cannot be significantly reduced and the rate of cell replication and division cannot be significantly reduced. Therefore, anti-aging cocktail therapies generally not only do not significantly extend the lifespan of mice, but also have serious side effects.

It doesn't work. Inflammation has certain benefits. Inflammation means that cells are aging or abnormal, and it tells the immune system to eat me up, thereby clearing out aging or abnormal cells. NR can inhibit inflammation, but DE. Harrison, et al. [1] pointed out that NR cannot extend the lifespan of mice. However, estradiol can extend the average lifespan of male mice by 19%; the macrophage migration inhibitory factor antagonist (MIF098) can help macrophages migrate and reduce chronic inflammation in the body [2]. However, MIF098 was not able to extend the lifespan of mice tested by the most authoritative National Institute on Aging in the United States [1]. Recently reported use of antibodies to inhibit the inflammatory factor IL-11 can extend the average lifespan of male mice by 22.5% and the average lifespan of female mice by 25% [3]. This is not because anti-inflammation can extend lifespan, but because inhibiting IL-11 can inhibit mTOR, thereby reducing cell replication and telomere shortening, which is equivalent to taking rapamycin. According to Bilu Huang's analysis, chronic inflammation is merely a consequence of aging mediated by P53 pathway caused by telomere and rDNA arrays shortening [4].

NMN, NR, and niacin all promote mitochondrial function, increase metabolic rate, and shorten lifespan. For example, the most authoritative US National Institute on Aging tested NR and found that it not only failed to extend the lifespan of mice, but also shortened their lifespan by 3% [1]. Niacin increases all-cause mortality and the risk of cardiovascular events by 10%.

The article “A New Era in Anti-Aging Research! NMN, the “Elixir of Life” Favored by Rich Businessmen and Scholars, Has the First Human Clinical Results in the World, Improving Metabolic Aging, but the Details Are Worrying” states that the world’s first randomized controlled double-blind human clinical trial was published in Science. In the supplementary materials not published in the main text, we can see that NMN did not cause any improvement in human muscle strength, endurance, or fatigue recovery speed. Although muscle insulin sensitivity was improved, other tissues in the body did not improve at all. Overall metabolic levels, from weight to body fat percentage, from blood pressure to blood sugar, from insulin levels to glycated hemoglobin and triglycerides, all indicators related to metabolic aging did not show any change. Going deeper, at the cellular level, NMN’s proud ability to improve mitochondrial function was also missing in the study. After taking NMN for 10 weeks, the mitochondrial respiratory capacity did not change at all [2].

On April 30, 2025, researchers from the University of Copenhagen published a research paper titled: NAD depletion in skeletal muscle does not compromise muscle function or accelerate aging in Cell Metabolism, a subsidiary of Cell. The study constructed an inducible skeletal muscle-specific nicotinamide phosphoribosyltransferase (Nampt) gene knockout (iSMNKO) mouse model to disrupt the biosynthesis of NAD in the skeletal muscle of adult mice, reducing NAD+ levels by 85%. However, the muscle mass, tissue integrity, contractility, and exercise performance of the mouse model were not affected. At the molecular level, NAD-depleted muscles showed normal transcriptome, proteome, and mitochondrial characteristics, as well as maintained normal DNA methylation levels. Even in the case of NAD depletion throughout life, systemic and muscle health markers remain at normal levels [3];

Reduced NAD+ concentrations are thought to be associated with metabolic, cardiovascular, and neurodegenerative diseases. A crossover, double-blind, randomized, placebo-controlled (PBO) trial tested 1 gram of NR daily for 8 weeks and found that plasma phosphorylated tau 217 (pTau217) decreased by 7%, while it increased by 18% in the placebo group. However, it did not show a significant improvement in overall cognitive function in patients with mild cognitive impairment. In conclusion, supplementation with NAD+ precursors is insufficient to produce clinically meaningful cognitive improvements [4].

Tests on mice failed to extend lifespan. Dipak K. Das, an Indian researcher studying resveratrol at the University of Connecticut, published over 150 papers over seven years, mostly demonstrating its positive effects in animal models. In 2012, his papers were found to contain over 145 falsifications. In 2008, pharmaceutical giant GlaxoSmithKline acquired Sirtris for $720 million. This company, founded by Harvard Medical School professor David Sinclair, was developing the anti-aging drug resveratrol. However, in GlaxoSmithKline's clinical trials, resveratrol failed to achieve the expected results, with some patients even experiencing kidney failure. After several years of fruitless research, GlaxoSmithKline disbanded Sirtris, debunking the myth of resveratrol's anti-aging potential.

Statistics show that metformin may prolong the lifespan of diabetic patients. Please note that the lifespan of diabetic patients is prolonged because of the therapeutic effect of metformin, but it is useless for healthy people and may even shorten their lifespan.

A study by Fudan University showed that metformin can extend the median lifespan of nematode larvae by 11.1%, but shorten the lifespan of old nematodes by 22.2% [1]. It has been reported that low-dose metformin (0.1%, about 10.6 mg/kg per day) extends the lifespan of mice by 6%, while high-dose (1%) shortens the lifespan by 14% [2]. On October 18, 2023, Professor Wang Fuyi of Zhejiang University School of Medicine and others published a research paper titled: Metformin Potentiates Nephrotoxicity by Promoting NETosis in Response to Renal Ferroptosis in the journal Cell Discovery. It was found that even low doses of metformin can aggravate experimentally induced acute kidney injury (AKI) in mice and increase their mortality [3]. Basal metabolic rate of different organ tissues (kcal/kg/day): fat 4; muscle 12; liver 182; brain 218; heart 400; kidney 400. It is suggested that the kidneys need to consume a large amount of ATP, and metformin can inhibit the production of ATP by mitochondria, so metformin is toxic to the kidneys; in a rigorous experiment conducted by the large-scale anti-aging drug testing program (ITP) launched by the National Institute on Aging (NIA), metformin also failed to extend the lifespan of mice [4]; a large-scale population study on the relationship between various drugs and human lifespan found that metformin has no effect on extending human lifespan [5].

It doesn't work. In 2023, Liu Guanghui, Qu Jing from the Institute of Zoology, Chinese Academy of Sciences, and Zhang Weiqi from the Beijing Institute of Genomics, Chinese Academy of Sciences, published a paper titled "Resurrection of endogenous retroviruses during aging reinforces senescence" in the top journal Cell [1]. It was also selected as one of the top ten scientific advances in China in 2023 under the title "Unveiling the mechanism of dark matter in the human genome driving aging." However, it was not found that reverse transcriptase inhibitors (NRTIs) can extend the lifespan of normal mice [2]. This is because the expression of ERVs is not the cause of aging, but the result of aging. Specifically, the expression of ERVs is caused by the increase in the level of tumor suppressor protein P53 [3].

It doesn’t work. Continuous AKG supplementation for seven months can turn back the human’s epigenetic clock by eight years [1]. However, AKG cannot extend the lifespan of male mice. It can only extend the average lifespan of middle-aged juvenile mice by 12% [2]. It is estimated that it is difficult to extend the maximum lifespan, which also shows that the epigenetic theory of aging mentioned above is wrong.

The lifespan extension is minimal, but the side effects are significant. There are four signaling pathways that affect lifespan. The insulin/IGF-1 and mTOR pathways accelerate protein synthesis, increase metabolic rate, and accelerate tissue cell renewal when food is plentiful, thus shortening lifespan. Conversely, the AMPK and Sirtuin pathways reduce protein synthesis, lower metabolic rate, and decrease tissue cell renewal when food is insufficient, thus extending lifespan.

Interfering with signaling pathways affects lifespan by influencing the rate of telomere and rDNA shortening, which limit the number of cell divisions. For example, activating mTOR accelerates cell replication, accelerating telomere and rDNA shortening and increasing replicative aging. Overeating in fruit flies accelerates rDNA copy loss. Activating mTOR in mice accelerates rDNA copy loss in hematopoietic stem cells. Activating sirtuins, on the other hand, silences telomeres and rDNA, reducing their shortening and thus reducing replicative aging.

In a paper titled "Taurine deficiency as a driver of aging," 14-month-old middle-aged mice were treated with taurine at a daily dose of 1000 mg/kg body weight. The median lifespan increased by 10% to 12%, and the life expectancy at 28 months increased by approximately 18% to 25%. The lifespans of the two control groups were 871 to 885 days for females and 785 to 815 days for males. Complete blood counts (CBCs) showed that taurine treatment reduced the number of white blood cells (WBCs), monocytes, and granulocytes, suggesting an immunosuppressive effect [1].

Taurine primarily affects the brain through GABAergic receptors. The resulting effects vary from person to person, ranging from drowsiness and brain fog to increased energy and alertness. Generally, a dose of 5g or less is safe. However, for a 65kg person, the anti-aging dose used in mice would require 65g of taurine daily, making it practically unsuitable for use as an anti-aging drug and potentially associated with significant side effects.

Recent studies have found that in healthy humans, non-human primates, and mice, taurine levels do not decrease with age, but instead increase or remain constant, suggesting that decreased taurine levels may not be related to aging [2].

In August 2025, researchers from McGill University in Canada and other institutions published an article titled "Experimental Evidence Against Taurine Deficiency as a Driver of Aging in Humans" in the journal Aging Cell [3]. The study found no association between circulating taurine levels and aging, muscle mass, strength, physical performance, or mitochondrial function. This study further challenged the theory that taurine deficiency is the primary driver of human aging.