Thanks to a generous matching challenge by Oculus co-founder Michael Antonov, up to 600,000 donated before the end of 2020 will be doubled! But wait, there's more. A team of SRF supporters - Brendan Iribe, Karl Pfleger, Jim Mellon, Dave Fisher, Christophe Cornuejols and Larry Levinson - have joined forces to offer a further 300,000 matching grant. This pool of funds runs in parallel to Michael's challenge, which means the next 300,000 donated will be tripled!

Currently there are 28+ anti-aging therapies in human clinical trials spanning a variety of strategies, targets, indications, companies, and modalities. The trials are conducted by companies - private and public - but also universities and non-profit groups. There are also perhaps 100 more pre-clinical companies working on aging in addition to this effort. If any one of the therapies in the first volley on the problem of aging achieve success - even if modest - it could trigger investor hype rivaling the biggest bubbles in history. The zero to one moment in human life extension will change everything.

With the exception of maybe Nir Barzilai's TAME metformin trial (not yet registered), none of the anti-aging therapies currently being tried directly use aging as their clinical endpoint. Most trials instead measure a therapy's efficacy with respect to a specific age-related disease rather than aging itself. Or sometimes the indication is a disease that can be treated with a tool developed from an aging perspective. This is because: (1) The FDA does not recognize aging as an indication (yet). (2) It is expensive to run trials that measure lifespan in humans. (3) We don't have have robust surrogate biomarkers for aging (yet). (4) It is easier to demonstrate clinical significance in an age-related disease than aging itself.

Aging is a malleable biological process. Scientists have been precisely turning the knobs of aging in model organisms since the 1990s. Presently we have reached an inflection point: Therapies developed in the context of longevity science are being tested in human patients today.

LYG-LIV0001 - LyGenesis

Perhaps one of the more ambitious clinical trials. LyGenesis is a Juvenescence-backed startup spun out of research at the University of Pittsburgh. The company is attempting to regrow livers by injecting allogenic liver cells into patient lymph nodes. The lymph nodes act as bioreactors and slowly regrow into functional livers - at least in the pre-clinical experiments done on pigs. Their Phase 2 trial includes patients with end-stage liver disease. If successful the company plans to also use the same strategy to regrow the thymus (reversing immunosenescence) and also pancreatic islet cells (reversing diabetes).

SkQ1 - Mitotech

Mitotech is an anti-aging company that develops therapies that protect the mitochondria from reactive oxygen species (ROS). SkQ1 is an anti-oxidant that can easily penetrate the mitochondrial membrane where it can inhibit ROS. In particular, SkQ1 protects cardiolipin, an important protein found in the inner mitochondrial membrane. Dry eye might not sound like a very sexy anti-aging therapy. But this trial is just one small step in the journey of treating mitochondrial diseases, many of which are age-related.

Nicotinamide riboside - ChromaDex

NAD+ levels decrease with age so the hypothesis is that boosting NAD+ levels can have potential anti-aging benefits. There are several chemical precursors to NAD+ but the two most popular are nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). ChromaDex is the patent holder of NR and sponsors a number of clinical trials to support the case for its potential anti-aging properties. This time they are measuring hospitalization duration for patients with tissue damage. Given the small size of the study (84 participants) and probable heterogeneity in the illnesses, I have a hard time seeing how anything definitive will be elucidated. This is just one trial of many exploring the benefits of NAD+ precursors / booster. These NAD+ precursor compounds are generally considered safe so I'm excited to see what can benefits can be demonstrated in trials.

Bone homeostasis in the adult skeleton is complex processes. Human skeletal tissue is a constant state of remodelling. The three main bone cells involve in this remodelling process - osteoblasts, osteoclasts and osteocytes via regulation of molecular signalling pathways. In bone remodelling, the discrete zones of bone are resorbed by osteoclasts and substituted by fresh bone by osteoblasts, allowing for repair of bone micro-injury and adapting of bone niche for control of mechanical strengths.

Osteoblast cells are energetic in protein synthesis and matrix secretion to preserve and form new healthy bones. Following mineralization of bone matrix, fully differentiated and matured osteoblasts become osteocytes and are implanted in the bone matrix. During bone remodelling process, mechanosensory cells, osteocytes act as bone orchestrators. This remodelling process is regulated by several local (e.g., growth factors, cytokines, chemokines) and systemic (e.g., estrogens) factors that all together subscribe for bone homeostasis.

In bone modelling process, i.e., during bone development and bone resorption stages, osteocytes act autonomously to fine-tune bone structure. Interestingly, in bone remodelling process, these cells act recycler to restore and keep skeletal health. After osteoclast-mediated bone resorption sequence, the eroded surface of trabecular bone is engaged by osteoblasts that make bone matrix and then undertake mineralization. Under normal physiological conditions of bone homeostasis, osteoclastic action is closely associated with osteoblastic action in such a way that the eroded bone is completely exchanged by fresh bone. Definitively, fluctuating this homeostatic equilibrium in favour of excessive osteoclast activity turns to bone pathological conditions such as osteoporosis, Paget's disease, rheumatoid arthritis (RA), osteoarthritis, and autoimmune arthritis.

Osteoporosis can be prevented and improved musculoskeletal health by using numerous pharmacotherapies such as biphosphonates; selective estrogen receptor modulators (SERMs); hormone therapies; strontium ranelate; denosumab (a human monoclonal antibody with specificity for RANKL); romosozumab (a monoclonal antibody that binds to and inhibits sclerostin) or stimulating bone formation called anabolic medications e.g., PTH preparations and calcitonin therapy have been verified the effects of increased bone mineral density and decreased risk of skeletal fractures.

However, these treatments have some side effects, such as oily skin, fluid retention, nausea, long-term toxicity, and even prostate cancer in males and thus natural therapies that incur better therapeutic activities and fewer side effects are hunted. Therefore, searching for small molecules that precisely suppress osteoclastic action is a favourable approach of the drug discovery for the treatment and management of bone-related diseases including osteoporosis.

Scientists have successfully restored vision in mice by turning back the clock on aged eye cells in the retina to recapture youthful gene function. The team used an adeno-associated virus (AAV) as a vehicle to deliver into the retinas of mice three youth-restoring genes - Oct4, Sox2, and Klf4 - that are normally switched on during embryonic development. The three genes, together with a fourth one, which was not used in this work, are collectively known as Yamanaka factors. The treatment had multiple beneficial effects on the eye. First, it promoted nerve regeneration following optic-nerve injury in mice with damaged optic nerves. Second, it reversed vision loss in animals with a condition mimicking human glaucoma. And third, it reversed vision loss in aging animals without glaucoma.

The team's approach is based on a new theory about why we age. Most cells in the body contain the same DNA molecules but have widely diverse functions. To achieve this degree of specialization, these cells must read only genes specific to their type. This regulatory function is the purview of the epigenome, a system of turning genes on and off in specific patterns without altering the basic underlying DNA sequence of the gene.

This theory postulates that changes to the epigenome over time cause cells to read the wrong genes and malfunction - giving rise to diseases of aging. One of the most important changes to the epigenome is DNA methylation, a process by which methyl groups are tacked onto DNA. Patterns of DNA methylation are laid down during embryonic development to produce the various cell types. Over time, youthful patterns of DNA methylation are lost, and genes inside cells that should be switched on get turned off and vice versa, resulting in impaired cellular function. Some of these DNA methylation changes are predictable and have been used to determine the biologic age of a cell or tissue. Yet, whether DNA methylation drives age-related changes inside cells has remained unclear. In the current study, the researchers hypothesized that if DNA methylation does, indeed, control aging, then erasing some of its footprints might reverse the age of cells inside living organisms and restore them to their earlier, more youthful state.

Ageing is a degenerative process that leads to tissue dysfunction and death. A proposed cause of ageing is the accumulation of epigenetic noise that disrupts gene expression patterns, leading to decreases in tissue function and regenerative capacity. Changes to DNA methylation patterns over time form the basis of ageing clocks, but whether older individuals retain the information needed to restore these patterns - and, if so, whether this could improve tissue function - is not known. Over time, the central nervous system (CNS) loses function and regenerative capacity. Using the eye as a model CNS tissue, here we show that ectopic expression of Oct4, Sox2, and Klf4 genes (OSK) in mouse retinal ganglion cells restores youthful DNA methylation patterns and transcriptomes, promotes axon regeneration after injury, and reverses vision loss in a mouse model of glaucoma and in aged mice. The beneficial effects of OSK-induced reprogramming in axon regeneration and vision require the DNA demethylases TET1 and TET2. These data indicate that mammalian tissues retain a record of youthful epigenetic information - encoded in part by DNA methylation - that can be accessed to improve tissue function and promote regeneration in vivo.

Epidemiological investigations have indicated that the muscle mass of the human body decreases by approximately 1.5% yearly after the age of 50 and by 2.5-3.0% yearly after the age of 60. The incidence rate of sarcopenia among individuals over 80 years old is as high as 50%. Studies have shown that a 10% decrease in muscle mass leads to a decrease in immune function and an increase in the risk of infection. A 20% reduction in muscle mass results in muscle weakness, a decreased ability to participate in activities of daily living, and an increased risk of falling. A 30% reduction in muscle mass results in disability, loss of independent living ability, and failure of wound and pressure ulcer healing. A 40% reduction in muscle mass results in a markedly increased risk of death from pneumonia, respiratory dysfunction, etc.

The main manifestations of sarcopenia in elderly individuals are a decreased cross-sectional area of muscle fibers and reduced muscle strength and function. Clinical studies have shown that the reduction in muscle mass is much greater in the lower limbs than in the upper limbs. Gait speed or the short physical performance battery (SPPB) are commonly used to assess muscle function. Muscle strength tends to decrease with age, as manifested by reduced grip strength and knee joint extension, weakened hip joint bending activity, decreased pace, and increased time to maximal muscle contraction compared with those of young individuals. Additionally, the number and the proliferation and differentiation abilities of muscle stem cells (MuSCs), which play an important role in muscle cell regeneration, are reduced. The number of MuSCs in aged mice is 50% lower than that in young mice.

A recent study found that CR can improve the function of adult stem cells, including the regeneration ability of skeletal MuSCs. To study whether CR can affect the rhythmic activity of stem cells during aging, researchers conducted a 25-week comparative observation of aged mice that consumed a control diet or a diet with 30% fewer calories than the control diet. In this study, except for the reduction in body weight, the aging characteristics related to epidermal and muscle tissue in mice were significantly ameliorated in the CR group compared with the control group. Additional studies have indicated that not stem cells themselves but the stem cell microenvironment is the key factor mediating stem cell activation, proliferation and differentiation.

Mitochondrial dysfunction is an important factor leading to age-related muscular atrophy. Considering the dependence of skeletal muscle on ATP, loss of mitochondrial function, which can lead to a decrease in strength and endurance, is especially obvious in skeletal muscle. CR can preserve the integrity and function of mitochondrial structure via reducing oxidative damage. Previous studies have shown that CR reduces proton leakage and ROS generation in mitochondria in skeletal muscle while enhancing the expression of ROS scavenging-related genes. In addition, CR may alter the fatty acid composition of the mitochondrial membrane, reduce lipid oxidation, and reduce proton leakage.

Accumulating evidence suggests that apoptosis may constitute a fundamental mechanism driving the onset and progression of sarcopenia. There are two main pathways of apoptosis: activation of the apoptotic enzyme caspase through extracellular signaling and activation of caspases through the release of mitochondrial apoptosis activators. These activated caspases can degrade important proteins in cells and induce apoptosis. The gene expression and cleavage of pre-caspase-3 in the gastrocnemius muscle were significantly reduced in CR mice compared with control mice. In addition, CR increased the content of apoptosis inhibitors in the cytoplasm.

Experimental data strongly suggest that mTOR activity increases during aging, beginning in middle age and resulting in progressively altered mitochondria, in turn leading to mitochondrial oxidative stress and thus the induction of catabolic processes, including protein degradation, apoptosis, and necrosis. This elevated catabolic activity results in muscle fiber loss, atrophy, and damage. Recent evidence has shown that CR downregulates mTORC1 signaling in skeletal muscle independent of dietary protein intake. Moreover, a paper published in 2019 indicated that the effects of CR on mTOR signaling in skeletal muscles are age-dependent. CR altered mTOR signaling in the soleus muscles in middle-aged rats but not in young and adult rats.

Autophagy is essential for overall cellular health because in some residual tissues, the lack of an autophagic response gradually results in the accumulation of damage within the cells, eventually leading to cell death and loss of tissue function. In vivo studies have demonstrated that CR can increase autophagic responses in skeletal muscle. Additional studies have shown that CR regulates the transcription factor Forkhead box O3 (FOXO3), which is associated with human longevity, and recent studies have shown that muscle atrophy is associated with the expression of the transcription factor FOXO3 and other downstream target skeletal muscle atrophy-related proteins.

In summary, the protective effects of CR on sarcopenia are manifested as improved protein quality, maintenance of muscle strength, and enhanced muscle function, and these effects may be achieved via mitigation of cellular oxidative stress, promotion of mitochondrial function, alleviation of the inflammatory response, inhibition of apoptosis, activation of autophagy, and other mechanisms.

Aging leads to a number of disorders caused by cellular senescence, tissue damage, and organ dysfunction. It has been reported that anti-inflammatory and insulin-sensitizing compounds delay, or reverse, the aging process and prevent metabolic disorders, neurodegenerative disease, and muscle atrophy, improving healthspan and extending lifespan. Here we investigated the effects of PPARγ agonists in preventing aging and increasing longevity, given their known properties in lowering inflammation and decreasing glycemia.

Our molecular and physiological studies show that long-term treatment of mice at 14 months of age with low doses of the PPARγ ligand rosiglitazone (Rosi) improved glucose metabolism and mitochondrial functionality. These effects were associated with decreased inflammation and reduced tissue atrophy, improved cognitive function, and diminished anxiety- and depression-like conditions, without any adverse effects on cardiac and skeletal functionality. Furthermore, Rosi treatment of mice started when they were 14 months old was associated with an 11% median lifespan extension.

A retrospective analysis of the effects of the PPARγ agonist pioglitazone (Pio) on longevity showed decreased mortality in patients receiving Pio compared to those receiving a PPARγ-independent insulin secretagogue glimepiride. Taken together, these data suggest the possibility of using PPARγ agonists to promote healthy aging and extend lifespan.

Obese patients over the age of 60 can lose an equivalent amount of weight as younger people using only lifestyle changes, according to a new study that demonstrates that age is no barrier to losing weight. The researchers hope that their findings will help to correct prevailing societal misconceptions about the effectiveness of weight loss programmes in older people, as well dispel myths about the potential benefits of older people trying to reduce their weight.

For this retrospective study, researchers randomly selected 242 patients who attended an obesity service between 2005 and 2016, and compared two groups (those aged under 60 years and those aged between 60 and 78 years) for the weight loss that they achieved during their time within the service. All patients had their body weight measured both before and after lifestyle interventions administered and coordinated within the obesity service, and the percentage reduction in body weight calculated across both groups.

When compared, the two groups were equivalent statistically, with those aged 60 years and over on average reducing their body weight by 7.3% compared with a body weight reduction of 6.9% in those aged under 60 years. Both groups spent a similar amount of time within the obesity service, on average 33.6 months for those 60 years and over, and 41.5 months for those younger than 60 years. The hospital-based program used only lifestyle-based changes tailored to each individual patient, focusing on dietary changes, psychological support, and encouragement of physical activity. Most of the patients referred to the obesity service were morbidly obese with a BMI typically over 40.

Aging has been associated with a myriad of both acute and chronic diseases. At the core of these diseases, the change in the host immune system with age could either have contributed to the cause as it is the host main defence mechanism against foreign pathogens or its functionality being impacted by these diseases and conditions. However, the change in the immune system with age could also be seen as an adaptation process to save resources for the host rather than it being detrimental.

This is because developing competent naïve T cells has only about 1-2% success rate due to the various stringent selection processes. Therefore, biological processes such as thymic involution could be seen as advantageous to the host from an energetic or evolutionary point of view. One of the main arguments that thymic involution is detrimental to the host is due to the reduction of naïve T cells being produced, leading to a narrower repertoire for new antigens and perhaps reduced vaccine efficacy often observed in the elderly, while this may have been a successful programmed process for the shorter-lived humans in the past centuries and before the extended human lifespan has revealed the probable need to reverse this adaptation.

Chronic low-grade inflammation is a commonality between individuals that exhibit chronic stress, obesity, aging, sleep loss, gut dysbiosis, CMV infection, dysregulated immune cell functions, and accumulation of SASP cells such as fibroblasts. Chronic low-grade inflammation is defined as a higher baseline of pro-inflammatory cytokines in the circulation though the source and specific cytokines might differ slightly between these "diseases" in the absence of foreign pathogen infection. In terms of impaired immunity, both human and animal studies have shown that chronic stress reduces various immune functional capacities. The presence of impaired immunity and low-grade chronic inflammation could be the underlying factors that exacerbate pathology in various disease contexts.

Thus, it is important that we redefine and stress that the definition of immunosenescence is the dysfunctionality of the immune system and should encompass some features of low-grade chronic inflammation. Though this phenomenon is often seen in aged individuals, it is also possible in younger adults as it could be "accelerated immunosenescence", especially for T cells, as shown in CMV and HIV seropositive young patients. Even early in life, the impact of CMV can be observed. This highlights that other factors other than chronological age could determine this level of senescence of the immune system, especially for T cells which are prone to proliferation. Overall, rethinking the causing agents and implications of immunosenescence will help shift the perspective that this phenomenon is not attributed to age alone, especially with the global rising rate of obesity and chronic stress of modern-day life in the young.

Nearly 15 years ago, researchers discovered that stem cells are drawn to inflammation, a biological "fire alarm" that signals damage has occurred. However, using inflammation as a therapeutic lure isn't feasible because an inflammatory environment can be harmful to the body. Thus, scientists have been on the hunt for tools to help stem cells migrate to desired places in the body. This tool would be helpful for disorders in which initial inflammatory signals fade over time - such as chronic spinal cord injury or stroke - and conditions where the role of inflammation is not clearly understood, such as heart disease.

In the study, the scientists modified CXCL12 - an inflammatory molecule which the team previously discovered could guide healing stem cells to sites in need of repair - to create a drug called SDV1a. The new drug works by enhancing stem cell binding and minimizing inflammatory signaling, and can be injected anywhere to lure stem cells to a specific location without causing inflammation.

To demonstrate that the new drug is able to improve the efficacy of a stem cell treatment, the researchers implanted SDV1a and human neural stem cells into the brains of mice with a neurodegenerative disease called Sandhoff disease. This experiment showed SDV1a helped the human neural stem cells migrate and perform healing functions, which included extending lifespan, delaying symptom onset, and preserving motor function for much longer than the mice that didn't receive the drug. Importantly, inflammation was not activated, and the stem cells were able to suppress any pre-existing inflammation.

The researchers have already begun testing SDV1a's ability to improve stem cell therapy in a mouse model of ALS, which is caused by progressive loss of motor neurons in the brain. Previous studies indicated that broadening the spread of neural stem cells helps more motor neurons survive, so the scientists are hopeful that strategic placement of SDV1a will expand the terrain covered by neuroprotective stem cells and help slow the onset and progressive of the disease.

The health benefits of dietary restriction have long been known. Recently, it has become clear that restriction of certain food components, especially proteins and their individual building blocks, the amino acids, is more important for the organism's response to dietary restriction than general calorie reduction. On the molecular level, one particular well-known signalling pathway, named TOR pathway, is important for longevity. "We wanted to know which factor is responsible for measuring nutrients in the cell, especially amino acids, and how this factor affects the TOR pathway. We focused on a protein called Sestrin, which was suggested to sense amino acids. However, no one has ever demonstrated amino acid sensing function of Sestrin in a living being."

"Our results in flies revealed Sestrin as a novel potential anti-ageing factor. We could show that the Sestrin protein binds certain amino acids. When we inhibited this binding, the TOR signalling pathway in the flies was less active and the flies lived longer. Flies with a mutated Sestrin protein unable to bind amino acids showed improved health in the presence of a protein-rich diet."

If the researchers increased the amount of Sestrin protein in stem cells located in the fly gut, these flies lived about ten percent longer than control flies. In addition, the increased Sestrin amounts only in the gut stem cells also protected against the negative effect of a protein-rich diet. "We are curious whether the function of Sestrin in humans is similar as in flies. Experiments with mice already showed that Sestrin is required for the beneficial effects of exercise on the health of the animal. A drug that increases the activity of the Sestrin protein might therefore be in future a novel approach to slow down the ageing process."

Extracellular vesicles (EVs) are membrane bound vesicles which vary from nanometer to micrometer in size and carry a diverse set of factors. Recently, our group investigated how circulating EVs change with age, the cell types responsible, and the response of these factors to rejuvenation therapies. Profiling of EV cargo revealed greater expression of inflammation-associated microRNAs such as miR-146a, miR-21, let-7a, and miR-223 in old plasma EVs compared with young. These microRNAs are predicted to target multiple intracellular signaling cascades which regulate cellular responses to external stimuli.

To determine the cell types responsible for changes in circulating EV microRNAs, we assessed EVs secreted by young and old peripheral blood mononuclear cells (PBMCs) in-vitro as well as plasma EVs isolated from old mice reconstituted with young or old bone marrow. However, EV microRNAs were similar in both models, suggesting that circulating cells have a minor contribution to the microRNAs identified this study. Further investigation into potential cell sources revealed that induction of senescence in-vitro and in-vivo, using gamma irradiation, mimicked the changes observed in old mice such as increased levels of circulating EVs and increased expression of EV associated miR-146a, mIR-21, and let-7a.

Interestingly, senolytic therapy using dasatinib + quercetin (D+Q) reduced the expression of these microRNAs in the plasma of old mice, supporting that senescent cells or the pathways targeted by these compounds contribute to increased expression in the circulation. Collectively, this data demonstrates that aging and cellular senescence leads to increased levels of circulating EVs, and that these EVs impair cellular responses to activation. Pharmacological targeting of senescent cells partially rejuvenated the microRNA profile and functional effects of old plasma EVs.

Senescent cells secrete cytokines, growth factors, and proteases which alter neighboring cell function. This secretome is collectively referred to as the senescent associated secretory profile (SASP) and the adverse effects of senescent cells are largely attributed to this profile. More recent definitions of the SASP have been expanded to include EVs. Secretion of EVs by senescent cells into the circulation could be one mechanism by which senescent cells promote cell dysfunction, as persistent uptake of senescent-EVs may lead to sustained changes in cellular function. Therefore, approaches aimed at targeting senescent cells may help reduce circulating senescent-EV levels and limit the impact senescent cells have on cells throughout the body.

New research has discovered a cell type that governs the way bones form and maintain themselves, opening up a potential target for future therapies for bone disorders like osteoporosis. A rodent study showed that bone marrow adipogenic lineage precursors (MALPs) play a distinct role in the way bones remodel themselves. Defects in this process are the key issue at play in osteoporosis, so a therapy using these MALP cells to better regulate bone remodeling could result in better treatments.

Healthy bone maintenance is a balance between osteoblasts, which secrete the materials necessary to form new bone, and osteoclasts, which absorb old bone material to make way for the new. A disruption in this balance one way or the other can result in unhealthy bone. In the case of osteoporosis, overactive osteoclasts eat away at bone faster than it can be reformed, resulting in bones that are less dense and more susceptible to fracture. The general consensus among scientists was that osteoblasts and osteocytes, the cells within fully-formed bone, were the ones that kicked off the production of osteoclasts to begin the remodeling of bone. On the other hand, the role of adipocyte lineage cells, such as MALPs, in regulating the resorption of bone was not known.

MALPs are the precursors for adipocytes that carry fats, called lipids, inside bone marrow. Recent studies better cleared up how MALPs appear to factor in bone turnover. They showed that MALPs, but not osteoblast or osteocytes, have cell-to-cell contact with osteoclasts. Additionally, using advanced sequencing techniques at a single cell level, researchers found that MALPs secrete RANKL, a protein essential for forming osteoclasts, at a high level.

With that information, researchers studied mice with RANKL deficiencies in their MALPs. From the point those mice turned a month old, the researchers saw 60 to 100 percent higher density of the spongy components of long bones (like the femur) and vertebrae, something the researchers qualified as "a drastic increase" compared to typical mouse bone mass. Since the osteoblasts and osteocytes continued to work as they always do, it would seem that MALPs and their RANKL secretions have been pinpointed as the main driver of osteoclast function and the absorption of existing bone.

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The book features first of its kind coverage of entirely new segments and sectors of the rising Longevity Industry, including Longevity Politics and Governance, the Longevity Financial Industry (including coverage of AgeTech, WealthTech, FinTech, and the coming rise of new financial instruments and derivatives), the current state and forecasts on the Global Industrialization of Longevity to Scale, and an overview of the near-future trajectory of the Longevity Industry's evolution 2020-2025.

The role of mitochondrial dysfunction in aging is well documented. The primary hallmarks of aging are defined as unequivocally deleterious to the cell. This means that proper functioning of these processes is important for the viability of the cell and the dysfunction that occurs with age leads to cellular damage. Mitochondrial dysfunction interacts with each of these primary hallmarks, thus leading to progression of the aging process.

The nine cellular and molecular hallmarks of aging are divided into three groups; (a) the primary hallmarks, (b) antagonistic hallmarks, and (c) integrative hallmarks. The primary hallmarks, which are unequivocally deleterious to the cell, include genomic instability, telomere attrition, epigenetic alterations, and loss of proteostasis. The antagonistic hallmarks, which are beneficial at low levels but at high levels become deleterious, are deregulated nutrient sensing, cellular senescence, and mitochondrial dysfunction. Finally, the integrative hallmarks, affecting tissue homeostasis and function, are stem cell exhaustion and altered intercellular communication. These hallmarks of aging have been presented throughout various research disciplines as nine separate hallmarks, and, while possessing crosstalk, are still considered largely independent. In this review, we provide evidence of the interplay between hallmarks, by highlighting one, mitochondrial dysfunction, and how it interacts with all others.

The hallmarks of aging connect to and influence one another. For instance, cellular senescence can be induced by genomic instability or telomere attrition and epigenetic alternations can lead to genomic instability. It is hence evident that the hallmarks of aging are not discrete entities as how are often presented, but instead operate in a large and tightly connected network. Targeting one factor of this network can result in affecting other hallmarks and thus influence the whole network of aging.

Although this complicates our interpretation of anti-aging interventions and requires a more holistic approach, it also opens opportunities for treatment options that not only target one hallmark but in fact act on the entire, or at least a large section of the network. In relation to the phylogenetic tree of life, while the exact details of the hallmarks of aging may differ, the main commonality that unifies aging across all species is the fact that all their hallmarks interconnect. Taking the entirety of this network into account will benefit the aging research community, and ultimately allow for a greater understanding of the aging processes and the progression of age-related disease.

Cells respond to a variety of factors, such as oxidative stress, DNA damage, and shortening of the telomeres capping the ends of chromosomes, by entering a stable and persistent exit from the cell cycle. This process, called cellular senescence, is important, as it prevents damaged cells from proliferating and turning into cancer cells. But it is also a natural process that contributes to aging and age-related diseases. Recent research has shown that cellular senescence can be reversed. But the laboratory approaches used thus far also impair tissue regeneration or have the potential to trigger malignant transformations.

Researchers used an innovative strategy to identify molecules that could be targeted for reversing cellular senescence. The team pooled together information from the literature and databases about the molecular processes involved in cellular senescence. To this, they added results from their own research on the molecular processes involved in the proliferation, quiescence (a non-dividing cell that can re-enter the cell cycle), and senescence of skin fibroblasts, a cell type well known for repairing wounds. Using algorithms, they developed a model that simulates the interactions between these molecules. Their analyses allowed them to predict which molecules could be targeted to reverse cell senescence.

They then investigated one of the molecules, an enzyme called PDK1, in incubated senescent skin fibroblasts and three-dimensional skin equivalent tissue models. They found that blocking PDK1 led to the inhibition of two downstream signalling molecules, which in turn restored the cells' ability to enter back into the cell cycle. Notably, the cells retained their capacity to regenerate wounded skin without proliferating in a way that could lead to malignant transformation. The scientists recommend investigations are next carried out in organs and organisms to determine the full effect of PDK1 inhibition. Since the gene that codes for PDK1 is overexpressed in some cancers, the scientists expect that inhibiting it will have both anti-aging and anti-cancer effects.