Why do we age? 14 hallmarks of aging

Researchers believe that aging can be explained by 14 hallmarks that underly the aging process. These hallmarks lead to various age-related diseases and conditions, such as heart disease, diabetes, and cancer, to name a few of them. There are nine well-established hallmarks of aging, ¹ Li, Zhe et al. “Aging and age-related diseases: from mechanisms to therapeutic strategies.” Biogerontology vol. 22,2 (2021): 165-187. PubMed Source with five more ² Schmauck-Medina, Tomas et al. “New hallmarks of ageing: a 2022 Copenhagen ageing meeting summary.” Aging vol. 14,16 (2022): 6829-6839. PubMed Source recently added to this list that provides a good overview of the mechanisms that answer the question of why we age. Let’s have a closer look at all of them and possible interventions to attenuate them.

What is it? Telomeres are meaningless DNA sequences found at the ends of chromosomes. They help protect the chromosomes from damage and ensure that DNA is properly replicated during cell division. ³ Chakravarti, Deepavali et al. “Telomeres: history, health, and hallmarks of aging.” Cell vol. 184,2 (2021): 306-322. PubMed Source Telomeres shorten over time due to the normal process of cell division, which is called telomere attrition. Over time, telomeres become shorter and shorter until they are entirely stripped away. At this point, the cell loses its ability to divide and becomes a so-called “senescent cell”, which loses its functions and cannot divide anymore. On average, human cells have a limited number of cell divisions (50 times), which is called the Hayflick Limit and is very important biologically. It helps to prevent cancer, which essentially is an uncontrollable growth of cells.

Implications for health and longevity. Telomere attrition plays a major role in aging and the development of age-related diseases. ⁴ Vaiserman, Alexander, and Dmytro Krasnienkov. “Telomere Length as a Marker of Biological Age: State-of-the-Art, Open Issues, and Future Perspectives.” Frontiers in genetics  vol. 11 630186. 21 Jan. 2021. PubMed Source It has been shown that telomere shortness can predict people’s statistical risk of developing certain conditions, such as cancer, dementia, obesity, diabetes, and even their mortality risk. ⁵ Blackburn, Elizabeth H, and Elissa S Epel. “Telomeres and adversity: Too toxic to ignore.” Nature vol. 490,7419 (2012): 169-71. PubMed Source The shorter the telomers are, the higher the risk is.

Therapeutic interventions are aimed at extending telomers’ length, which has the potential to rejuvenate many types of cells. However, these therapies should be designed with caution to avoid the risk of cancer. Some gene therapies focused on transferring telomerase, an enzyme that extends and maintains telomeres, are shown to have promising results. Intranasal and injectable forms of telomerase have been shown to increase the mouse lifespan by 41%. ⁶Jaijyan, Dabbu Kumar et al. “New intranasal and injectable gene therapy for healthy life extension.” Proceedings of the National Academy of Sciences of the United States of America vol. 119,20 (2022) PubMed Source This therapy also improved glucose tolerance and physical performance and prevented loss of body mass and alopecia.

Lifestyle interventions: Although we inherit the telomers’ length from our parents, some lifestyle choices greatly impact telomere length. Among them are:

1. Diet. ⁷ Leung, Cindy W et al. “Soda and cell aging: associations between sugar-sweetened beverage consumption and leukocyte telomere length in healthy adults from the National Health and Nutrition Examination Surveys.” American journal of public health vol. 104,12 (2014): 2425-31. PubMed Source Telomere length is positively associated with consuming legumes, nuts, seaweed, fruits, dairy products, and coffee. It is inversely associated with the consumption of alcohol, red meat, or processed meat.
2. Stress level. ⁸ Lin, Jue, and Elissa Epel. “Stress and telomere shortening: Insights from cellular mechanisms.” Ageing research reviews vol. 73 (2022): 101507. doi:10.1016/j.arr.2021.101507 PubMed Source Chronic psychological stress is associated with shorter telomeres. So finding your best ways of stress management and practicing mindfulness can be very beneficial.
3. Physical activity. ⁹ Arsenis, Nicole C et al. “Physical activity and telomere length: Impact of aging and potential mechanisms of action.” Oncotarget vol. 8,27 (2017): 45008-45019. PubMed Source Regular aerobic exercise slows down the process of telomere shortening. ¹⁰ Song, Seonghyeok et al. “Does Exercise Affect Telomere Length? A Systematic Review and Meta-Analysis of Randomized Controlled Trials.” Medicina (Kaunas, Lithuania) vol. 58,2 242. 5 Feb. 2022. PubMed Source

What is it? Senescence is a state of permanent cell cycle arrest when the cell stops dividing and turns into a so-called senescent zombie cell. Senescence can be triggered by various factors, such as damage to DNA or mitochondria, shortening of telomeres, changes in the epigenome, inflammation, and oxidative stress. Although senescent cells are not dividing, they are metabolically active and secrete different inflammatory toxins. This phenomenon is called the senescence-associated secretory phenotype (SASP). It is associated with all the negative consequences of senescence on the body. ¹¹ van Deursen, Jan M. “The role of senescent cells in ageing.” Nature vol. 509,7501 (2014): 439-46. PubMed Source

Implications for health and longevity. Senescent cells accumulate in the body as we age, and the amount of the inflammatory toxins they produce also increases over time. This contributes to many age-related diseases and the overall decline in function that occurs with aging. For example, senescence and SASP significantly worsen conditions such as Alzheimer’s, heart disease, osteoporosis, frailty, and liver fibrosis.

Therapeutic interventions aim to remove senescent cells or suppress their secretory phenotype (SASP). The therapeutic agents that selectively kill senescent cells in the body are called senolytics (such as dasatinib, quercetin, and fisetin). Alternatively, the agents that suppress the secretion of inflammatory toxins are called senomorphics, including some widely-used medicines, like rapamycin and metformin. Both senolytics and senomorphics are very effective in improving the function of individual tissues and the health span in general. ¹² Lagoumtzi, Sofia M, and Niki Chondrogianni. “Senolytics and senomorphics: Natural and synthetic therapeutics in the treatment of aging and chronic diseases.” Free radical biology & medicine vol. 171 (2021): 169-190. PubMed Source Some of these drugs are already in clinical trials, possibly representing a future treatment of age-related pathologies, including atherosclerosis, osteoarthritis, osteoporosis, cancer, diabetes, Alzheimer’s disease, and cardiovascular diseases.

Lifestyle interventions.

1. Physical exercise can reduce the inflammatory markers of senescent cells in the blood. ¹³ Chen, Xiang-Ke et al. “Is exercise a senolytic medicine? A systematic review.” Aging cell vol. 20,1 (2021): e13294. PubMed Source 
2. Caloric restriction without malnutrition is currently the most effective non-genetic intervention to delay aging, and it decreases cellular senescence. ¹⁴ Maduro, Ana T et al. “Ageing, cellular senescence and the impact of diet: an overview.” Porto biomedical journal vol. 6,1 e120. 11 Feb. 2021. PubMed Source
3. Some natural senolytic supplements (like quercetin, fisetin, piperlongumine, and curcumin) are available over the counter or can be added to the diet as spices. However, the research on the action mechanisms of senolytic supplements and recommended dosage is still ongoing.

Therapeutic interventions: Since the main underlying factor of genomic instability is compromised DNA repair, all anti-aging and anti-cancer research aims to find agents that stabilize the genome and restore DNA repair capabilities. ¹⁶ Burgess, Joshua T et al. “The Therapeutic Potential of DNA Damage Repair Pathways and Genomic Stability in Lung Cancer.” Frontiers in oncology vol. 10 1256. 28 Jul. 2020. PubMed Source

Lifestyle interventions. One of the most effective ways to support the health of your genome is to maintain a healthy lifestyle. ¹⁷ Satia, Jessie A et al. “Diet, lifestyle, and genomic instability in the North Carolina Colon Cancer Study.” Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology vol. 14,2 (2005): 429-36. PubMed Source ¹⁸ Cheung, V et al. “The effect of sleep deprivation and disruption on DNA damage and health of doctors.” Anaesthesia vol. 74,4 (2019): 434-440. PubMed Source This includes the following:

1. Balanced diet.
2. Regular physical activity.
3. Avoiding tobacco and excessive alcohol consumption.
4. Regular good-quality sleep.
5. Certain supplements, such as antioxidants, can potentially help to protect against genome instability and other age-related changes, but the evidence is heterogenic.

What is it? Epigenetic alterations are changes in gene expression that are not caused by changes in the underlying DNA sequence. The epigenome is the information that our cells have in addition to our DNA code. The epigenome consists of small chemical compounds connected to the DNA, called methylation groups. They are important for determining which genes are switched on or off in every tissue and organ in our body. Additionally, DNA is wrapped around proteins called histones. Along with methylation, histones also determine what parts of DNA will be expressed. Over time, the tight package of DNA around histones is disrupted, causing changes in DNA expression. Environmental factors (toxins, radiation, stress, diet, and different diseases) lead to epigenetic alterations that build up as we age, altering how our DNA is expressed.

Implications for health and longevity. Accumulation of epigenetic changes causes disruption in gene expression involved in important biological processes. This, in turn, leads to the malfunction of different cells in the body and gradual development of age-related diseases.

Therapeutic interventions: Resetting the epigenetic tags to their original state can stimulate cells to repair damage on their own, reversing aspects of the aging process. Some of the compounds have shown promising results in their ability to modify the epigenetic material. For example, calcium alpha-ketoglutarate (AKG) has been shown to reverse the epigenetic clock in humans by up to 8 years. ¹⁹ Demidenko, Oleksandr et al. “Rejuvant®, a potential life-extending compound formulation with alpha-ketoglutarate and vitamins, conferred an average 8 year reduction in biological aging, after an average of 7 months of use, in the TruAge DNA methylation test.” Aging vol. 13,22 (2021): 24485-24499. PubMed Source Another molecule, resveratrol, is able to activate sirtuins, a group of enzymes that regulate lifespan in part through the regulation of gene expression. ²⁰ Kanfi, Yariv et al. “The sirtuin SIRT6 regulates lifespan in male mice.” Nature vol. 483,7388 218-21. 22 Feb. 2012. PubMed Source

Lifestyle interventions. The epigenome can be greatly influenced by the environment and lifestyle choices. ²¹ Alegría-Torres, Jorge Alejandro et al. “Epigenetics and lifestyle.” Epigenomics vol. 3,3 (2011): 267-77. PubMed Source  Among them are:

1. Obesity, so keeping your weight in a healthy range is very important.
2. Physical activity.
3. Tobacco smoking, alcohol consumption, and environmental pollutants detrimentally affect the epigenome.
4. Chronic psychological stress negatively affects the epigenome.
5. Working night shifts alter epigenetic material.

What is it? Proteostasis is a carefully regulated process of synthesis, folding, maintaining, and breaking down proteins in the body. During aging, this process gets disrupted, and a disbalance between protein synthesis and protein degradation occurs, causing aggregation of misfolded harmful proteins. Partly, it happens due to the impairment of autophagy, the cellular mechanism of breaking down old damaged proteins. And partly due to the upregulation of protein synthesis through mTOR signaling pathways, which are responsible for regulating growth, cell proliferation, and protein synthesis.

Implications for health and longevity. The aggregation of damaged or misfolded proteins can form clumps that can interfere with cellular function and contribute to developing diseases such as Alzheimer’s, Parkinson’s, and various forms of cancer.

Therapeutic interventions are aimed at the restoration of proteostasis by activation of autophagy and downregulation of mTOR pathways. Studies showed that autophagy activators and mTOR inhibitors, such as rapamycin and spermidine, could extend the lifespan of yeast, nematodes, fruit flies, and mice. ²² Li, Zhe et al. “Aging and age-related diseases: from mechanisms to therapeutic strategies.” Biogerontology vol. 22,2 (2021): 165-187. PubMed Source

Lifestyle interventions. You can downregulate the mTOR signaling pathway and stimulate autophagy through diet interventions, ²³ Drummond, Micah J, and Blake B Rasmussen. “Leucine-enriched nutrients and the regulation of mammalian target of rapamycin signaling and human skeletal muscle protein synthesis.” Current opinion in clinical nutrition and metabolic care vol. 11,3 (2008): 222-6. PubMed Source such as:

1. Calorie restriction.
2. Fasting.
3. Cutting down on meat.

What is it? Deregulated nutrient sensing is a disturbance in the body’s ability to properly regulate and respond to nutrients, such as amino acids, glucose, and fatty acids. This happens due to changes in the main signaling pathways that are involved in nutrient sensing. So far, four of these main pathways with corresponding responsible proteins are well-described:

• insulin-like growth factor-1 (IGF-1) protein is involved in the metabolism of proteins;
• mTOR protein is activated by amino acids coming from food sources (e.g. meat);
• sirtuins are proteins activated by nutrient scarcity and fasting,
• AMP-activated protein kinase (AMPK) is activated in response to low levels of ATP (the energy currency of cells).

The first two proteins, IGF-1, and mTOR, are associated with food abundance, and they are involved in anabolism (building tissues), growth, and storage. Whereas the last two, sirtuins and AMPK, are activated by food and energy scarcity and responsible for maintaining homeostasis. With aging, nutrient sensing becomes compromised, contributing to the development of age-related diseases.

Implications for health and longevity. Deregulated nutrient sensing results in changes in metabolism, leading to a range of diseases, such as reduced insulin sensitivity and obesity, loss of muscle mass, inflammation, impaired wound healing, and development of cataracts.

Therapeutic interventions. Downregulation of the pathways involved in anabolism, such as IGF-1 and mTOR, and activating pathways involved in homeostatic regulation, such as sirtuins and AMPK, promote longevity. Many pharmaceutical agents target these pathways. For example, rapamycin inhibits the mTOR pathway mimicking the effect of food scarcity; metformin activates AMPK signaling pathways mimicking energy scarcity. ²⁴ Li, Zhe et al. “Aging and age-related diseases: from mechanisms to therapeutic strategies.” Biogerontology vol. 22,2 (2021): 165-187. PubMed Source

Lifestyle interventions. Diet interventions are very effective in affecting nutrient-sensing pathways. They downregulate mTOR and IGF-1 pathways and activate the body’s self-cleansing processes (autophagy). In addition, they also activate sirtuins and AMPK longevity pathways. ²⁵ Blasiak, Janusz et al. “The Aging Stress Response and Its Implication for AMD Pathogenesis.” International journal of molecular sciences vol. 21,22 8840. 22 Nov. 2020. PubMed Source

These interventions include:

1. Calorie restriction.
2. Cutting down on meat.
3. Intermittent fasting.

What is it? Stem cell exhaustion refers to a decline in the body’s function and number of stem cells during aging. Stem cells are undifferentiated cells that can give rise to all specialized cell types of our bodies. They are found in many tissues and organs in the body and play a vital role in tissue repair and regeneration.

Implications for health and longevity. As we age, stem cells number gradually diminishes in all the tissues, which causes loss of regenerative ability by these tissues. For example, with aging, the activity of hematopoietic stem cells decreases, leading to a reduced adaptive immune response to viruses and bacteria and an increased risk of anemia. Similar processes happen in all the organs and tissues, gradually leading to the loss of proper functioning of these organs and tissues.

Therapeutic interventions aim to replace stem cells through cell therapies or by stimulating divisions of existing stem cells. This area of medicine is called regenerative medicine, which aims to reverse the aging process by targeting stem cells. Animal models show very promising results. The transplantation of stem cells from young mice to old mice extended their lifespan and improved tissue function, possibly due to the systemic effects of the factors secreted by young stem cells. ²⁶ Lavasani, Mitra et al. “Muscle-derived stem/progenitor cell dysfunction limits healthspan and lifespan in a murine progeria model.” Nature communications vol. 3 608. 3 Jan. 2012. PubMed Source That is why regenerative medicine and stem cells have become the main focus of biomedical research in recent years. However, despite the enormous potential of stem cell therapy in fighting age-related disorders and promoting longevity, further research is needed to understand the mechanisms underlying stem cells fully. Nowadays, stem cell therapy is actively used by doctors in cancer treatment, known as bone marrow transplants. They use adult stem cells or umbilical cord blood cells for this purpose. Stem cells replace cells damaged by chemotherapy or disease, facilitating the fight against some types of cancer (such as leukemia, lymphoma, neuroblastoma, and multiple myeloma). Numerous clinical trials are undergoing to test the efficacy of regenerative medicine for treating neurodegenerative diseases, endocrine and reproductive disorders, skin regeneration, pulmonary dysplasia, and cardiovascular diseases.

Lifestyle interventions. Some lifestyle interventions can boost your stem cell proliferation, including:

1. Calorie restriction and cutting on sugars.²⁷ Lo, Ting et al. “Glucose reduction prevents replicative senescence and increases mitochondrial respiration in human mesenchymal stem cells.” Cell transplantation vol. 20,6 (2011): 813-25. PubMed Source
2. Aerobic exercise.²⁸ Joanisse, Sophie et al. “The Impact of Aerobic Exercise on the Muscle Stem Cell Response.” Exercise and sport sciences reviews vol. 46,3 (2018): 180-187. PubMed Source
3. Some supplements, such as vitamin C, D, resveratrol, and curcumin.²⁹ Abdelbaset-Ismail, Ahmed et al. “Vitamin D3 stimulates embryonic stem cells but inhibits migration and growth of ovarian cancer and teratocarcinoma cell lines.” Journal of ovarian research vol. 9 26. 18 Apr. 2016. PubMed Source ³⁰Sharifi, Simin et al. “Stem Cell Therapy: Curcumin Does the Trick.” Phytotherapy research : PTR vol. 33,11 (2019): 2927-2937. PubMed source ³¹Safaeinejad, Zahra et al. “Multi-effects of Resveratrol on stem cell characteristics: Effective dose, time, cell culture conditions and cell type-specific responses of stem cells to Resveratrol.” European journal of medicinal chemistry vol. 155 (2018): 651-657. PubMed Source

What is it? Mitochondrial dysfunction refers to a decline in the function of mitochondria, which are small organelles found in cells that play a critical role in energy production. Mitochondria produce energy in the form of ATP (adenosine triphosphate). The efficiency of the mitochondria declines with aging, resulting in reduced ATP levels, increased apoptosis (cell death), and increased production of harmful byproducts called reactive oxygen species (ROS). There are several theories as to why mitochondria dysfunction may occur with age. One theory is that as we age, the mitochondria accumulate damage and mutations in their DNA, which can affect their function. Another theory is that the mitochondria become less efficient at repairing themselves as we age, leading to a decline in their function.

Implications for health and longevity. Some studies suggest that mitochondria dysfunction may be a critical factor in age-related diseases such as Alzheimer’s disease, Parkinson’s disease, and cardiovascular disease.³² Bell, Simon M et al. “Mitochondrial Dysfunction in Alzheimer’s Disease: A Biomarker of the Future?.” Biomedicines vol. 9,1 63. 11 Jan. 2021. PubMed Source It is also thought to be a key factor in the decline of physical function and the development of age-related conditions such as sarcopenia (loss of muscle mass) and frailty. ³³ Ferri, Evelyn et al. “Role of Age-Related Mitochondrial Dysfunction in Sarcopenia.” International journal of molecular sciences vol. 21,15 5236. 23 Jul. 2020.

Therapeutic interventions. Several therapeutic interventions are being developed or are currently being tested for their potential to address mitochondria dysfunction and potentially slow the aging process. Some supplements, such as nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), coenzyme Q10, and resveratrol, are thought to support the function of the mitochondria and alleviate aging processes. Future therapeutic interventions will be directed at stabilizing genetic and epigenetic data of mitochondrial DNA.

Lifestyle interventions. The following interventions may delay mitochondrial aging and attenuate age-related changes:³⁴ Amorim, João A et al. “Mitochondrial and metabolic dysfunction in ageing and age-related diseases.” Nature reviews. Endocrinology vol. 18,4 (2022): 243-258.

1. Caloric restriction.
2. Regular physical training.

What is it? Altered intercellular communication refers to changes in how cells communicate with each other during aging. Communication between cells is essential for the proper functioning of tissues and organs. It occurs through various means, including direct contact between cells or soluble factors (hormones, chemical, and neurochemical signaling).

Direct contact between cells gets attenuated in aging due to changes in the extracellular matrix, a network of proteins and other molecules surrounding cells and providing structural support. With age, this matrix becomes less organized and unable to support cells, leading to changes in intercellular communication. ³⁵ Schüler, Svenja C et al. “Extensive remodeling of the extracellular matrix during aging contributes to age-dependent impairments of muscle stem cell functionality.” Cell reports vol. 35,10 (2021): 109223. PubMed Source Another contributing factor to altered intercellular communication is a change in signaling pathways. For example, insulin and growth hormone signaling pathways get attenuated, leading to disruption in metabolism. In addition, an overall increase in inflammatory molecules happening during aging disrupts intercellular communication.

Implications for health and longevity. Altered intercellular communication contributes to the breakdown of tissues and organs, leading to a decline in function and an increased risk of age-related diseases. In particular, it plays a key role in developing chronic inflammation associated with various health problems, such as cardiovascular disease, diabetes, and cancer.

Therapeutic interventions. Restoring neurochemical and hormonal signaling to a more youthful state can benefit overall health and longevity. It has been shown that some agents, such as metformin ³⁶ Chen, Sheng et al. “Metformin in aging and aging-related diseases: clinical applications and relevant mechanisms.” Theranostics vol. 12,6 2722-2740. 6 Mar. 2022. PubMed Source and resveratrol, ³⁷ Santos, Milena Almeida et al. “Resveratrol has its antioxidant and anti-inflammatory protective mechanisms decreased in aging.” Archives of gerontology and geriatrics vol. 107 (2023): 104895. PubMed Source can improve intercellular communication.

Lifestyle interventions.

1. Regular physical exercise is one of the most efficient lifestyle interventions for improving intercellular communication and decreasing overall inflammation. Several authors associated lifelong aerobic exercise training with lower inflammatory levels, especially with lower levels of C-reactive protein, IL-6, and TNF-α, particularly in advanced decades of life. ³⁸ [Nicklas, Barbara J, and Tina E Brinkley. “Exercise training as a treatment for chronic inflammation in the elderly.” Exercise and sport sciences reviews vol. 37,4 (2009): 165-70. PubMed Source ³⁹ Beavers, Kristen M et al. “Effect of exercise training on chronic inflammation.” Clinica chimica acta; international journal of clinical chemistry vol. 411,11-12 (2010): 785-93. PubMed Source
2. Supplements, such as resveratrol. ⁴⁰ Santos, Milena Almeida et al. ⁴⁰“Resveratrol has its antioxidant and anti-inflammatory protective mechanisms decreased in aging.” Archives of gerontology and geriatrics vol. 107 (2023): 104895. PubMed Source

What is it? Compromised autophagy is one of the most recently added hallmarks of aging. Compromised autophagy refers to a situation in which the autophagy process is impaired or not functioning correctly. As it was described above, autophagy is very important for cleaning the body of accumulating cellular waste and misfolded proteins.

Implications for health and longevity. With aging, autophagy becomes impaired, contributing to numerous aging conditions, including neurodegeneration (especially Alzheimer’s), cancer, cardiovascular disease, and other age-related conditions.

Therapeutic interventions. Some autophagy activators, such as rapamycin and spermidine, could extend the lifespan of yeast, nematodes, fruit flies, and mice. ⁴² Juricic, P., Lu, YX., Leech, T. et al. Long-lasting geroprotection from brief rapamycin treatment in early adulthood by persistently increased intestinal autophagy. Nat Aging 2, 824–836 (2022). Source In humans, rapamycin is used for treating many forms of cancer due to its anti-proliferative properties. In healthy individuals, using rapamycin mimics the effects of caloric restriction. However, the wide use of this medicine for life-extension purposes is doubtful because of its potentially dangerous side effects. ⁴³ Li, Jing et al. “Rapamycin: one drug, many effects.” Cell metabolism vol. 19,3 (2014): 373-9. PubMed Source

Lifestyle interventions.

1. Diet interventions such as intermittent fasting, especially for longer periods of time (such as thee-day fasting), can activate autophagy and boost natural detoxification processes in the body. ⁴⁴ Elsayed, Hassan Reda Hassan et al. “Independent of Calorie Intake, Short-term Alternate-day Fasting Alleviates NASH, With Modulation of Markers of Lipogenesis, Autophagy, Apoptosis, and Inflammation in Rats.” The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society vol. 69,9 (2021): 575-596. PubMed Source  2. Exercise stimulates autophagy in the body ⁴⁵ Halling, Jens Frey, and Henriette Pilegaard. “Autophagy-Dependent Beneficial Effects of Exercise.” Cold Spring Harbor perspectives in medicine vol. 7,8 a029777. 1 Aug. 2017. PubMed Source

What is it? Microbiome disturbance refers to changes in the composition and function of the gut microbiome that occur over time. The gut microbiome is the community of microorganisms that live in the gastrointestinal tract. It plays a critical role in many aspects of health, including digestion, immune function, metabolism, and aging. As we get older, the gut microbiome’s composition also changes. But in less healthy people, these changes are minor or not occurring at all, and their gut microbiome remains relatively static. It was linked to a higher mortality rate among these people. ⁴⁶ Wilmanski, Tomasz et al. “Gut microbiome pattern reflects healthy ageing and predicts survival in humans.” Nature metabolism vol. 3,2 (2021): 274-286. PubMed Source So, a changing microbiome that adjusts appropriately to an aging body benefits health and lifespan. Although we share about one-third of bacterial species, our microbiome becomes increasingly more unique to us with age. And this uniqueness is positively associated with longevity. On the contrary, some harmful shifts in microbial populations and loss of species diversity are associated with increased inflammation.

Implications for health and longevity. Microbiome disturbance has been linked to a number of health issues, including chronic inflammation, immune system dysfunction, and a range of age-related diseases such as cardiovascular disease, diabetes, and cancer.

Therapeutic interventions. Current medical approaches are directed at restoring intestinal microbiota balance by using different probiotics, prebiotics, synbiotics and microbial replacement therapies. ⁴⁷ Gagliardi, Antonella et al. “Rebuilding the Gut Microbiota Ecosystem.” International journal of environmental research and public health vol. 15,8 1679. 7 Aug. 2018. PubMed Source The future direction of the anti-aging therapeutics focused on microbiomes is developing tailored probiotic cocktails to tackle age-related diseases. ⁴⁸Bosco, Nabil, and Mario Noti. “The aging gut microbiome and its impact on host immunity.” Genes and immunity vol. 22,5-6 (2021): 289-303. PubMed Source

Lifestyle interventions. Lifestyle factors that affect our microbiome the most include:

1. A fiber-rich diet supports the “good” bacteria and maintains diversity in your gut. ⁴⁹ Cronin, Peter et al. “Dietary Fibre Modulates the Gut Microbiota.” Nutrients vol. 13,5 1655. 13 May. 2021. PubMed Source
2. Antibiotics. It’s important to use them sensibly, only when it’s needed, as they are major disruptors of the gut microbiome. ⁵⁰Patangia, Dhrati V et al. “Impact of antibiotics on the human microbiome and consequences for host health.” MicrobiologyOpen vol. 11,1 (2022): e1260. PubMed Source
3. Regular physical activity has a positive effect on the gut microbiota. ⁵¹ Clauss, Matthieu et al. “Interplay Between Exercise and Gut Microbiome in the Context of Human Health and Performance.” Frontiers in nutrition vol. 8 637010. 10 Jun. 2021. PubMed Source

What is it? Altered mechanical properties refer to both intercellular and extracellular changes happening with aging. The most well-described intracellular change is the loss of nuclear lamina integrity, a protective barrier between the cell nucleus where DNA is stored and its surrounding, called cytoplasm. This causes the leakage of genetic information from the nucleus into the cytoplasm, triggering the secretion of inflammatory molecules.

The most well-known extracellular change is cross-linking of collagen through a process called glycation. This results in a loss of tissue elasticity and changes cell-to-cell communication in our organs and tissues, including skin wrinkles as the most visible sign of this.

Implications for health and longevity. Disruption of cytoskeletal integrity is associated with many age-related diseases, including dementia, diminished reproductive potential, and chronic inflammation.

Therapeutic interventions are directed at developing drugs that stabilize a cell’s cytoskeleton preserving its mechanical properties and integrity (Geerts, 1996, Kim, 2022)

Lifestyle interventions. Avoiding exposure to environmental toxins is the most effective way of preserving cells’ mechanical properties and integrity. For example, it has been shown that cigarette smoke significantly reduces cytoskeletal stability. ⁵²Kim, Yu Jin et al. “Links of Cytoskeletal Integrity with Disease and Aging.” Cells vol. 11,18 2896. 16 Sep. 2022. PubMed Source 

What is it? Splicing dysregulation refers to impairments in the splicing process that synthesizes RNA from DNA. Splicing is needed for further synthesis of protein from RNA (see the figure below). So, if splicing is impaired, protein synthesis also gets disturbed.

Implications for health and longevity. Splicing impairments are observed in older people (Holly, 2013) and greatly contribute to cellular senescence. Disrupted splicing is a major characteristic of many common chronic age-related diseases, such as cancer, neurodegenerative disease, osteoarthritis, cardiovascular disease, frailty, and sarcopenia (Harries, 2022).

Therapeutic interventions. Given the mechanistic links between disrupted splicing regulation and senescence, the therapeutic approaches are directed toward developing drugs to attenuate cellular senescence. In addition, some studies indicate on beneficial effects of resveratrol on the splicing process. ⁵³ Markus, M Andrea et al. “Resveratrol, by modulating RNA processing factor levels, can influence the alternative splicing of pre-mRNAs.” PloS one vol. 6,12 (2011): e28926. PubMed Source

Lifestyle interventions that can positively affect RNA splicing attenuating age-related changes include:

1. Caloric restriction.⁵⁴ Bhadra, Malini et al. “Alternative splicing in aging and longevity.” Human genetics vol. 139,3 (2020): 357-369. PubMed Source 
2. Dietary supplement, resveratrol.

What is it? Age-dependent chronic inflammation, often called “Inflamm-Aging,” refers to the increased levels of inflammation and high levels of inflammatory molecules in the blood, such as interleukin-1 (IL-1), IL-6, C-reactive protein, interferon alpha (IFNα), and several others. Given the large contribution of general inflammation to the aging process, it has recently been given its place among the hallmarks of aging. Still, it is greatly interconnected with other hallmarks, such as cellular senescence, gut microbiome, and altered intercellular communication. There are many theories about why inflammation rises when we age. Still, they all agree on the fact that this is a result of disruption in the relationship between inflammation and immunity.

Implications for health and longevity. Chronic inflammation is involved in a wide range of age-related diseases, as shown in the picture below. ⁵⁵ Leonardi, Giulia C et al. “Ageing: from inflammation to cancer.” Immunity & ageing : I & A vol. 15 1. 19 Jan. 2018. Besides this, chronic inflammation greatly contributes to constant feelings of fatigue, depression, anxiety, weight loss/gain, and gastrointestinal problems.

Therapeutic interventions. Different therapeutic approaches have been developed aiming at lowering overall inflammation in the body. The most common are nonsteroidal anti-inflammatory drugs and steroids. However, due to their side effects when used long-term, they are mostly used for treating acute disorders and can’t be considered anti-aging agents. Some supplements, such as curcumin ⁵⁶ Panahi, Yunes et al. “Adjuvant therapy with bioavailability-boosted curcuminoids suppresses systemic inflammation and improves quality of life in patients with solid tumors: a randomized double-blind placebo-controlled trial.” Phytotherapy research : PTR vol. 28,10 (2014): 1461-7. PubMed Source and lipoic acid, [ efn_note] Moura, Fabiana Andréa et al. “Lipoic Acid: its antioxidant and anti-inflammatory role and clinical applications.” Current topics in medicinal chemistry vol. 15,5 (2015): 458-83. PubMed Source [/mfn] has been shown to decrease systemic inflammation in cancer patients. Still, their effect on systemic inflammation in healthy people has not been studied well.

Lifestyle interventions.

1. Diet. Some studies indicate that sufficient antioxidants in food may improve immune function, decrease oxidative stress, and extend lifespan. ⁵⁷ Marchal, Julia et al. “Resveratrol in mammals: effects on aging biomarkers, age-related diseases, and life span.” Annals of the New York Academy of Sciences vol. 1290 (2013): 67-73. PubMed Source
2. Aerobic exercise lowers inflammation levels in the body, including lower levels of C-reactive protein, interleukin (IL-6), and tumor necrosis factor – α (TNF-α) ⁵⁸ Nicklas, Barbara J, and Tina E Brinkley. “Exercise training as a treatment for chronic inflammation in the elderly.” Exercise and sport sciences reviews vol. 37,4 (2009): 165-70. PubMed Source
3. Keeping your weight under control. Chronic inflammation is associated with obesity. ⁵⁹ Ellulu, Mohammed S et al. “Obesity and inflammation: the linking mechanism and the complications.” Archives of medical science : AMS vol. 13,4 (2017): 851-863. PubMed
4. Managing stress well. Chronic stress suppresses immune function and elevates levels of inflammation. ⁶⁰ Liu, Yun-Zi et al. “Inflammation: The Common Pathway of Stress-Related Diseases.” Frontiers in human neuroscience vol. 11 316. 20 Jun. 2017. PubMed Source