Senotherapy: The battle for quality vs quantity of life

Introduction

By the year 2050, more than 2 billion individuals will be over age 60.¹ At the same time, advances in healthcare and standards of living have resulted in an increase in lifespan for people throughout much of the world. While that is positive news, these increases in lifespan have not been matched by increases in healthspan, frequently resulting in a longer period of decreasing function and increasing susceptibility to chronic disease at the end of life.² Rates of chronic conditions such as diabetes, cardiovascular disease and Alzheimer’s disease (AD) all remain elevated.³ For example, 86% of over 85s in the UK have at least one chronic condition.⁴ The question therefore arises whether it is preferable to improve the human condition by reducing morbidity or by extending lifespan (or, ideally, both)?

The concepts of aging and longevity have been widely discussed in scientific literature going all the way back to the 16^th century, when physician philosopher Girolamo Cardano wrote about possible strategies to slow down the aging process.⁵ With the 20th century arrived theories, such as the free radical theory of aging, where aging results due to cellular damage from reactive oxygen species (ROS) generation.⁶

While aging is an incredibly complex process involving many pathways, more current theories suggest it may not necessarily be a fixed immutable phenomenon. Aging can be heterogenous between individuals depending on genetics, environment and pathology. In fact, organs within the same body can even age at different rates. The concepts of biological age and chronological age are now seen as distinct physiological parameters.⁷

As such, if biological age can possibly be manipulated, then age-associated diseases (AADs) such as Alzheimer’s, osteoarthritis and cancer could be delayed or potentially avoided altogether. In addition, economic assessments show that a slowdown in aging that increases life expectancy by 1 year is worth US$38 trillion, and by 10 years, US$367 trillion.⁸

Source: Towards Healthy Longevity - Comprehensive Insights from Molecular Targets and Biomarkers to Biological Clocks

The COVID pandemic, which highlighted the vulnerability posed to individuals by unhealthy aging and chronic disease, helped propel a large influx of investment and interest into the longevity industry. Although currently viewed as a more peripheral area of healthcare, it may soon become a competitor to disease-centered care.^8-1

This increased recognition of aging as being a deterioration of homeostatic mechanisms and a driver of disease that could possibly be manipulated and modified, instead of a simple inevitability, has led to the growth of geroscience, a new subsection of geriatric medicine. Headed by institutions such as the National Institute of Aging (NIA), a division of the US National Institutes of Health, whose sole aim is to enhance healthspan.⁹

In many individuals suffering from chronic disease, an accelerated aging process has taken place, where the biological age of their cells and tissues is further advanced than their chronological age. Geroscience aims to invert this relationship rather than focus on simply lengthening the human lifespan.⁹

What is senescence?

The title of a recent editorial, “Cellular senescence: beneficial, harmful, and highly complex” ¹⁰ is quite revealing. Senescent cells play critical roles for maintaining a healthy physiology but they also promote ageing and certain pathological conditions (including developmental disorders). Cellular senescence has been implicated in a host of age-associated diseases (AADs) including Chronic Kidney Disease (CKD), cataracts, glaucoma, Parkinson’s disorder (PD), Alzheimer’s Disease (PD), immunosuppression and osteopenia. There is a building rationale for senescent cells as a therapeutic target for disorders across the lifespan and promising strategies are beginning to come in focus ^10-1.

Types of senescence

Cellular senescence is defined as the state of decreased metabolic activity and the cessation of division. These cells exhibit a resistance to growth stimuli and apoptosis. Senescence can be replicative, where shortening of the telomeres of chromosomes from successive divisions has led to a cessation of division. Senescence can also be induced through exposure to stressors such as toxins or DNA damage. In both cases, replicative senescence and stress-induced premature senescence (SIPS) are thought to be natural anti-tumour mechanisms to halt cells at risk of malignant transformation. Such cells are usually cleared by the immune system.^10-2

Acute senescence is transient and beneficial in normal biological processes. It has a key role in wound healing and the development of placental syncytiotrophoblasts during pregnancy.¹¹

Chronic senescence, on the other hand, is a pathological process which has arisen through evasion of clearance by the immune system and often results in local tissue inflammation and dysfunction.

There are other types of senescence, notably paracrine senescence which is communicable between cells/body compartments. Conversely, attenuating senescence in for example the liver can also bring benefits for brain, kidney and lung. ^11-1.

Features of senescent cells

As part of the senescence process these cells undergo specific morphological changes - senescent-associated heterochromatin foci (SAHF) separate genes promoting proliferation and hide excessive DNA damage causing the cessation of division and the prevention of apoptosis. The changes in gene expression include an upregulation of cyclin-dependent kinase inhibitors such as p16 and p21, which are regulated by tumor suppression protein p53. Older mitochondria which have accumulated damage, produce ROS which further exacerbate cellular stress and DNA damage. The successive discoordination of cellular homeostatic processes including autophagy and protein modification results in excessive dysfunctional mitochondria and lysosomes.

Additionally, senescent cells release a cocktail of pro-inflammatory molecules and this senescent-associated secretory phenotype (SASP) creates a pro-inflammatory environment impairing the function of nearby cells and contributing to the pathogenesis of disease.^10-2

The SASP’s capability to negatively influence surrounding cells appears to vary with senescent cell sub-types. With senescent endothelial cells, pre-adipocytes and fibroblasts having a stronger SASP compared to senescent epithelial cells and myoblasts.¹²

A question of biomarkers

While there are many distinct features of senescence, there exists no universally agreed biomarker, which complicates the discovery and validation process for senotherapies. Levels of Beta-galactosidase (SA-β-gal) are raised in senescent cells due to accumulation of lysosomal units. However, raised SA-β-gal levels are also expressed by hair follicles, sebaceous glands and activated macrophages. Low levels of the nuclear envelope protein, lamin B1, is also associated with induction of senescence. Additionally, the previously mentioned cell-cycle inhibitors and components of the SASP such as IL-6 or IGFBP7 can also be measured.¹³

Clinically, SASP factors are measured in plasma. SA-β-gal, p16 and p21 expression is measured in tissue samples. However, many of these senescence or age deviation biomarkers lack specificity and can be raised in other pathological or physiological states. The current methods for their measurement are costly. To combat this issue, organisations such as the NIA and the Ageing Biomarker Consortium (ABC) are currently driving research to establish human biomarkers of aging. Furthermore, the EU commission has funded a large population study, the MARK-AGE project, to develop a collection of weighted criteria to measure ageing instead of using a single biomarker.⁷ Artificial Intelligence could also accelerate the identification and characterisation of aging.¹⁴

Anti-aging strategies

Senescence can be mitigated organically. These approaches include calorie restriction and regular intense physical activity. These lifestyle interventions arguably have the greatest efficacy of any anti-ageing intervention through the activation of many rejuvenating mechanisms.¹⁵ However, these strategies have poor adherence on a populational level and thus agents that mimic the effects of these lifestyle interventions tend to garner more interest from longevity venture capital funds and biotech start-ups.⁹

The identification of cellular senescence as a common culprit in many AADs has driven a minor frenzy in both drug development and consumer product markets to mitigate cellular senescence.

Supplements such as nicotinamide adenine dinucleotide (NAD+) boosters and other vitamins are widely consumed for their age-targeting effects. However, these presumed positive effects have failed to manifest in clinical trials with little evidence of improvement especially in already healthy individuals.¹⁶ Senotherapeutics, on the other hand, are drugs that specifically target ageing pathways and show strong potential for clinical translation.⁷

Senotherapeutics can be divided between a range of compounds, principally:

1. Senolytics – selectively eliminate senescent cells.

• Examples: dasatinib; quercetin
• Mechanism of action: selectively eliminate senescent cells.

2. Senomorphics – inhibit components of SASP without killing cells. For example, specific inhibitors of NF-κB signalling, a master modulator of inflammatory pathways. These are relatively understudied despite the SASP being recognised as a key driver of senescence.

• Examples: none currently.
• Mechanism of action: inhibit components of SASP without killing cells.

3. Geroprotectors - these compounds do not specifically target senescence pathways but rather have systemic benefits which in turn slow down the onset of senescence for example, rapamycin and other molecular target of rapamycin (MTOR) inhibitors.

• Examples: rapamycin, metformin.
• Mechanism of action: systemic benefits which slow down the onset of senescence.

4. Other compounds - Other possible compounds include autophagy promoters, mitophagy-inducers, protein quality control modulators or NAD+ boosters although many therapeutic agents modulate these pathways simultaneously such as metformin or rapamycin.⁷ Examples of these include autophagy promoters, protein quality control modulators and NAD+ boosters, with mechanisms of action that seek to selectively modulate different pathways that maintain cellular homeostasis.

Cancer and senescence

Senescence, while originally a cancer defense mechanism, may promote aggression and recurrence of cancers. Treatment of senescence alongside cancer treatment may therefore improve survival and reduce treatment toxicity.

Cancer treatment as a mechanism of senescence

Numerous anti-cancer therapies have been demonstrated to contribute to the development of senescence through stress-induced premature senescence (SIPS). This includes most chemotherapeutic agents, such as doxorubicin and cisplatin; radiotherapy; CKD4/6 inhibitors, such as palbociclib and ribociclib; epigenetic modulators, such as 5-Aza-2’ deoxycytidine and SAHA; and immunotherapies such as rituximab. Senescence markers are often present beyond 12 months post-treatment, indicating a chronic senescence picture with cells refractory to clearance.¹⁷

In fact, treatment-induced senescence (TIS) has been implicated as a possible mechanism for metastasis and the recurrence of more aggressive malignancies later in life.¹⁸

With regards to chemotherapeutic agents, TIS occurs in both normal and malignant cells. TIS from systemic treatments could result in senescent cell generation all around the body including non-target areas, contributing to chronic disease development. Indeed, studies often demonstrate cancer survivors have a much higher biological age compared to their healthy counterparts. It is worth noting that many studies involving TIS have used plasma SA-β-gal as the sole indicator for senescence.¹⁹

The SASP may be a more reliable indicator, indeed the SASP has been found in the lungs post-cancer treatment. This is important as lung damage and pulmonary inflammation are major clinical issues that prevent completion of treatment courses and exacerbate outcomes. Senescence may contribute to the toxicity and poor tolerance of systemic cancer treatment.²⁰

Friend or Foe?

While it may seem counter-intuitive that a natural defence mechanism against cancer may exacerbate its lethality, senescence seems to be a double-edged sword. On the one hand, the pro-inflammatory factors produced in the SASP may attract immune cells to tumors or prevent tumorigenesis. On the other hand, components of the SASP could also promote oncogenesis through IL-6 and IL-8 secretion by impairing immunosurveillance through recruitment of myeloid-derived suppressor cells, by increasing the invasiveness of cancer cells through STAT3 and MMP activation and by the promotion of epithelial-mesenchymal transformation (EMT) and stimulation of angiogenesis through VEGF release. Through these mechanisms, senescent cells in the tumor micro-environment (TME) can make cancers more aggressive and increase treatment-toxicity ultimately worsening disease-free survival.²¹ The difference between senescent cells being protective or detrimental may be related to their sub-type and their SASP.¹²

Source – 12, The Emerging Role of Senotherapy in Cancer: A Comprehensive Review

Cancer cells can themselves become senescent following cancer treatment. These cells, now no longer dividing, are refractory to treatment and can evade immune detection through SASP production until, long after a treatment course has finished, they regain stemness properties and are able to reinitiate their cell cycle, this time with resistance to previous treatments. For these reasons senescent cancer cells have been found to be highly connected to cancer relapse and more aggressive cancer sub-types.¹²

A one-two punch

Senotherapy could therefore have a place in combination with oncological therapies to minimise risk of relapse. Senotherapies have been demonstrated in vitro and in vivo to improve cancer treatment efficacy.¹² Senotherapy could be deployed alongside cancer therapy in a one-two punch combination. Younger patients with a lower senescent cell burden could be given adjuvant senotherapy after treatment to clear out senescent cells formed from cancer therapy. Older patients could be given neo-adjuvant senotherapy before cancer therapy to eliminate senescent cells in the TME, thus enhancing the cancer cell killing potential of chemotherapy or immunotherapy.¹⁸

Strategies utilising nanoparticles (NPs) could be used to further increase the selectivity of Senotherapies for senescent cells and enhance drug delivery. For example, agents can be encapsulated in galacto-oligosaccharide so the drug can be released in cells with high SA-β-gal.²² This has already been demonstrated to increase the specificity and decrease the platelet toxicity of, the BCL-2 inhibitor, navitoclax in vivo.²³

However, there remains many questions to be answered on senescence and cancer. Future research needs to take place to further elicit the relationship between cellular senescence and cancer outcomes and to find which senotherapeutic agents work best for each indication.

Senotherapies for AADs (excluding cancer)

The senescence-disease connection

Senescence has been implicated with a host of AADs:

• Senescent cells have been found to be present in CKD and senotherapy has restored renal function in ageing mice.²⁴
• High levels of senescent lens stem cells increase the development of cataracts.²⁵
• Retinal ganglion cell senescence has been found to be the main driver of degeneration in glaucoma.²⁶
• Senescence has been linked in numerous studies to the development of Alzheimer’s disease and Parkinson’s disease.²⁷
• Cellular senescence has also been linked to the depression of immune function associated with age through upregulation of PD-L1 positive cells and elimination of senescent cells has been shown to prevent age-related bone loss in mice.^28,29
• Usage of qasatinib and quercetin to eliminate senescent cells improves metabolic markers and reduced obesity in mice however this same combination failed to prevent progression of hepatic steatosis in mice.^30,31

Aging hallmarks such as cellular senescence, genomic instability and DNA damage are intertwined. Thus, a drug targeting one of these hallmarks can positively influence the others. For example, rapamycin inhibits the mechanistic target of rapamycin (mTOR), a nutrient sensing protein which modulates cellular senescence and autophagy pathways.³² Metformin, a diabetes drug, on the other hand,, activates AMP-activated protein kinase which has downstream effects of mTOR inhibition and increased lifespan.³³

Some anti-ageing strategies aim to increase healthspan through the utilisation of regenerative stem cell therapies and microbiome modulation, which do not necessarily exert their therapeutic benefits through specific cellular pathways.

Limitations of senolytics

It is worth noting that the current generation of senolytics are not without flaws. For example, dasatinib and quercetin, while having been found in multiple animal studies to be improve markers of obesity have also been found in other studies to have little therapeutic potential and to have toxic effects on platelets.^30,31 This ambiguity with senotherapeutic agents promotes scepticism and doubt.

The associated toxicity of senolytics may possibly be counteracted through optimising dosing regimes. Senolytics have a particular advantage as it takes 6 weeks for cellular senescence to develop again after clearance thus medications can be taken using a hit-and-run/intermittent approach, e.g., several days of taking the senolytic followed by a break period rather than constant administration.³⁴

A regulatory quandary

The FDA remains reluctant to designate aging as an indication for drug development. This is partly because a fixed framework for the validation of an anti-aging compound has not yet been elucidated.³⁵ This is in conflict with the philosophy of many high-profile longevity start-ups who consider aging a soon-to-be-treatable disease and the major risk factor for most chronic conditions.

Selling and marketing an anti-aging supplement, of course, does not face these barriers and for this reason compounds like fisetin and resveratrol are freely available. Ultimately, as supplements are not subject to the same quality assurance process as marketed drugs there is no guarantee of efficacy or safety.³⁶

The arguments of these longevity players are obfuscated by the lack of consensus on biomarkers. Biomarkers have been highlighted as important surrogate measures of drug efficacy in chronic diseases by the FDA. As discussed earlier, the biomarkers of senescence can simply resemble that of inflammation observed in many other diseases.

The TAME trial, a 6-year double-blind randomized controlled trial of metformin in non-diabetic older adults, hopes to elucidate some clear biomarkers, as well as demonstrate the anti-aging effect of metformin, a widely-prescribed diabetes drug which has been associated with lower rates of cancer, cardiovascular disease and all-cause mortality. This trial has a mixed-endpoint design to solve the issue of high variability of first age-related pathology onset between individuals.³⁷ The main measured outcomes of the trial include death and onset of multiple age-related diseases.³⁸

There are many notable players in the senotherapeutic industry, with a diversity of approaches to slowing down the ageing process and reducing the onset of chronic disease. Due to the current FDA outlook on anti-aging therapies, many industry players have focussed on developing therapies with sufficient efficacy against a major chronic disease such as diabetic macular edema, to receive FDA approval. They hope with time, sufficient clinical data can be accumulated to demonstrate that these agents positively influence aging biomarkers and improve healthspan, when the FDA decide to designate aging as an indication.³⁹ Many of these players are discussed in the table below.

Notable preclinical companies

One notable player who is taking an alternative approach worth mentioning is Loyal. This company hopes to develop a longevity drug in canines, which, if shown to exert its therapeutic effects via a pathway that is shared with humans, could then be rolled out for human patients. Such an approach may be able to demonstrate results sooner due to the shorter lifespans of dogs, especially in larger breeds.⁴⁰

SENISCA, a spinout company from Exeter University based on 15 years of academic work has centered its portfolio of molecules around a novel cellular pathway that modules cellular rejuvenation. SENISCA utilizes a proprietary RNA technology to develop therapeutics targeting RNA splicing regulation, which becomes dysregulated in senescence and can be used for multiple indications.⁴¹

Altos Labs is a company which gained recent notoriety despite having no clinical candidates. The company with a focus on understanding cellular reprogramming and rejuvenation emerged from stealth with $3bn raised from investors like Jeff Bezos. The philosophy of Altos Labs appears to be the enticement of leading figures within the longevity world with generous salaries and more scientific freedom. This figures include Richard Klausner, former chief of the National Cancer Institute, Shinya Yamanaka, Nobel Prize winner for his discovery of Yamanaka reprogramming factors and Manuel Serrano.⁴²

Longevity clinical trials

The table below highlights clinical trials that are being led by companies who have publicly outlined their intentions to fight aging or have received repeated recognition by longevity-centric venture capital funds such as the Longevity fund:

Outcomes key

Positive results
Mixed results
Negative Results
Results not available (still ongoing)

Trial ID	Indication/Disease	Drug	Phase	Outcomes	Additional notes
NCT02432287	Metabolic health	Metformin	4		Albert Einstein College of Medicine
NCT06181227	AMD	AVD-104	3		Aviceda
NCT05740813	ALS	Fosigotifator/ABBV-CLS-7262	3		Calico Life Sciences, AbbVie
NCT03928184	Knee OA	Lorecivivint	3		BioSplice Therapeutics
NCT03309007	Autophagy	Metformin	3		University of New Mexico
NCT06011798	DMO	UBX1325/foselutoclax	2		Unity Biotechnology
NCT05975983	IPF	INS018-055 (TNIK-inhibitor, anti-fibrotic agent)	2		InSilico Medicine
NCT05626114	GA in AMD	OpRegen (RPE cells derived from allogenic hESCs)	2		Roche/Lineage Cell Therapeutics
NCT05275205	nAMD	UBX1325	2		Unity Biotechnology
NCT04907253	Post-CABG outcomes	Q	2		Montreal Heart Institute
NCT04857996	DMO	UBX1325 (BCL-xl inhibitor)	2		Unity Biotechnology
NCT04771611	COVID-19	Fisetin	2		Mayo Clinic
NCT04733534	Cancer Survivor Frailty	D+Q AND Fisetin	2		St Jude Children’s Research Hospital
NCT04685590	EARLY AD/MCI	D + Q	2		Wake Forest University Health Sciences
NCT04537299	COVID-19	Fisetin	2		Mayo Clinic
NCT04476953	COVID-19	Fisetin	2		Mayo Clinic
NCT04369430	PD	AKST-4290 (non-plasma-derived agent)	2		Alkahest
NCT04331730	AMD	AKST-4290 (non-plasma-derived agent)	2b		Alkahest
NCT04313634	Osteopaenia	D+Q and Fisetin	2		Mayo Clinic
NCT04313634	Bone Health	D+Q	2		Mayo Clinic
NCT04063124	AD	D+Q	2		University of Texas, Mayo Clinic
NCT03981419	Post-arthroplasty recovery	ALK-6019 (plasma-derived)	2		Alkahest
NCT03765762	Severe AD	ALK-6019 (plasma-derived)	2		Alkahest
NCT03713957	PD	ALK-6019 (plasma-derived)	2		Alkahest
NCT03675724	Frailty	Fisetin	2		Mayo Clinic
NCT03520998	Mild-Moderate AD	ALK-6019 (plasma-derived)	2		Alkahest
NCT03430037	Frailty	Fisetin	2		Mayo Clinic
NCT02848131	Diabetic CKD	D+Q	2		Mayo Clinic
NCT00764309	IPF + Systemic Sclerosis	Dasatinib (TRKI)	2		Bristol Myers Squib
NCT05422885	MCI	D+Q	1/2		Hebrew Senior Life
NCT05025956	Post hip surgery outcomes	Fisetin + Losartan	1/2		Steadman Philippon Research Institute (US Department of Defense collaboration)
NCT04815902	OA knee	Fisetin + Losartan	1/2		Steadman Philippon Research Institute
NCT04229225 NCT04129944 NCT04349956 NCT03513016	Knee OA	UBX0101	1/2		Unity Biotechnology
NCT04210986	Knee OA	Fisetin	1/2		Steadman Philippon Research Institute
NCT01339884	Friedrich’s Ataxia	Jotrol (Resveratrol)	1/2		Jupiter Neurosciences
NCT04537884	DMO/AMD	UBX1325 (BCL-xl inhibitor)	1		Unity Biotechnology
NCT02874989	IPF	D+Q	1		Wake Forest University Health Sciences, Mayo Clinic
NCT02874924	Elderly health	Rapamycin	1		University of Texas Health Science Centre at San Antonio
NCT02652052	Frailty	D+Q	n/a		Mayo Clinic
NCT02256306	Mild AD	IV Plasma from Young Donors (Parabiosis)	n/a		Alkahest/ Stanford

Clinical trials highlights:

• Metformin in Longevity Study (MILES) led by Albert Einstein College of Medicine – This was double-blind placebo-controlled clinical trial with 14 participants that demonstrated daily metformin use in elderly people with impaired glucose tolerance had altered gene expression profiles in muscle and adipose tissue linked to ageing.⁴³
• Metformin Pro-Autophagy and Anti-Ageing study led by University of New Mexico – This Phase 3 interventional study successfully showed that Metformin boosted autophagy through increasing LC3 Convertase levels in Leukocytes.⁴⁴
• Lorecivivint for knee Osteoarthitis (OA) led by Biosplice Therapeutics – This Phase 3 trial for moderate to severe symptomatic knee OA was initiated in 2019 and the first patient received intra-articular injection in June 2019. Lorecivivint inhibits cdc-like kinase 2 (CLK2) and dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). Initial trial results (OA-11) showed little difference between intervention and placebo groups with regards to joint space width and pain scores however extension trials such as OA-7 were able to demonstrate over two years that there was significant stabilisation of joint space and evidence of slowed structural deterioration. Additionally, there were also improvements in pain and function reported by patients.⁴⁵
• Fosigotifator for Amyotrophic Lateral Sclerosis (ALS) led by Calico Life Sciences in partnership with AbbVie – fosigotifator is an elF2B activator developed by Calico, a Google spinout focussed on slowing down ageing. Calico also took an ‘Altos labs-like’ philosophy of hiring the top figures in the industry at the time. elF2B is an enzyme that modulates the integrated stress response and reduced activity has been implicated in ageing. The drug has also been selected for the FDA START Pilot Program for Vanishing White Matter Disease.⁴⁶
• UBX1325 for Ophthalmological indications including Diabetic Macular Oedema (DMO) and neovascular age-related macular degeneration led by Unity Biotechnology – UBX1325 is a BCL-xl inhibitor that promotes apoptosis of senescent cells and Unity Biotechnology’s lead candidate. It is administered intravitreally in phase II trials for multiple age-related ophthalmological diseases. Positive results such as improvements in visual acuity in DMO patients have been presented.^47,48,49,50
• AVD-104 for geographic atrophy (GA) in age-related macular degeneration led Aviceda Therapeutics – this is a sialic acid nanoparticle that attenuates neutrophil and macrophage-driven inflammation in the retina. Part 1 of the Phase 2 trial showed a good safety profile alongside improved visual acuity in patients with geographic atrophy and so Part 2 of the trial is ongoing which will measure GA area growth rate over 12 months compared to avacincaptad.⁵¹
• Dasatinib and quercetin (D+Q), multiple institutions – The tyrosine receptor kinase inhibitor dasatinib and the MTOR and PI3K inhibitor quercetin were the first drugs discovered by the hypothesis-driven approach to senolytic agent discovery. D+Q is currently undergoing phase II trials in individuals with diabetic kidney disease using the hit and run approach, a preliminary report indicated that markers of the SASP and other senescence markers were decreased, the study will also evaluate frailty and renal function after 14 days.⁵² Dasatinib and/or quercetin are also undergoing Phase II trials in Osteopaenia, Alzheimer’s disease and Frailty in Childhood Cancer survivors.^53,54,55 It is worth noting that dasatinib and quercetin have been trialed in patients with idiopathic pulmonary fibrosis with mixed success. Bristol Myers Squib used Dasatinib in patients with IPF and Scleroderma, which showed no significant clinical efficacy and perhaps worsened outcomes in a subset of patient with an inflammatory gene-expression profile.⁵⁶ In Mayo Clinic’s trial in 14 participants with stable IPF, D+Q improved physical function such as walking distance and gait speed but did not affect pulmonary function or clinical chemistry parameters. Additionally, SASP factors seemed unaltered.⁵⁷
• INS018-055 for Idiopathic pulmonary fibrosis (IPF) led by InSilico Medicine – This Hong Kong-based AI drug discovery company is back by Nvidia and uses its large AI drug-discovery platform to design new agents for multiple domains including anti-ageing. INS018-055 was one of the compounds produced by the platform which is an anti-fibrotic and TNIK inhibitor being investigated for IPF in a Phase II trial estimated to complete in 2026.⁵⁸
• OpRegen for Geographic Atrophy in dry age-related macular degeneration (AMD) led by Lineage Cell Therapeutics – Lineage Cell Therapeutics in partnership with Roche and Genentech has developed human embryonic stem cell-derived retinal pigment epithelial cells which when delivered surgically to AMD patients with GA has been shown to improve visual function and retinal structure for up to 4 years in a Phase I trial. They are currently recruiting for a phase IIa trial.^59,60
• AKST-4290 for Parkinson’s Disease and AMD led by Alkahest – This is an antagonist of CCR3 that blocks the action of eotaxin, an inflammatory mediator that accumulates in the blood during age-related inflammation. AKST-4290 has demonstrated improved visual acuity in wet AMD patients when taken orally, this differs to most AMD treatments which require intravitreal injections. Trials were also ongoing in diabetic retinopathy and bullous pemphigoid but were terminated due to safety findings in other trials or operational challenges.^61,62
• Fisetin for COVID-19, Osteopenia and Frailty led by Mayo Clinic – Fisetin is a natural flavonoid supplement which has been demonstrated to reduce senescent cell burden. Mayo Clinic is leading phase II trials for COVID-19 in 3 different patient populations including hospital patients (which will measure COVID severity), elderly care-home residents and at-risk patients. Mayo Clinic are also investigating Fisetin’s impact on frailty in older adults and specifically older women.^63,64,65,66
• Fisetin for a range of Orthopaedic indications led by Steadman Philippon Research Institute – Due to fisetin’s senolytic ability it is theorised that the supplement could improve bone and cartilage healing and recovery post-intervention. Fisetin is being investigated in combination with losartan in Knee Osteoarthritis patients who have received a stem cell injection in a phase II trial of 100 patients. The Institute in collaboration with the US department of defence are investigating this same combination for patients who have undergone hip arthroscopy and platelet rich plasma injection for femoroacetabular impingement and labral tear. The institute is also investigating fsetin’s direct impact on knee osteoarthritis patients in Phase 1/2 trial through senescence markers and patient-reported outcomes.^67,68,69
• UBX0101 for Knee Osteoarthritis led by Unity Biotechnology – UBX0101 was an MDM2 inhibitor (MDM2 inhibits the pro-apoptotic protein p53) administered via intra-articular injection for moderate-severe knee OA. However, interim results at 12 weeks for a phase II trial revealed the drug failed to meet the primary endpoint of improved pain scores compared to placebo. Unity Biotechnology subsequently discontinued the drug and chose to focus on its ophthalmological candidate, UBX1325, instead. As UBX0101 was the company’s lead asset at the time, its stock dropped more than 60% and nearly one-third of Unity staff were laid off. The failed trial also had wider ramifications for the entire longevity domain as UBX0101 was the first senolytic to enter clinical trials. In retrospect, UBX0101 may have failed for a number of reasons. One reason being the pro-apoptotic effect of UBX0101 was too potent to be administered systemically. It is known that senotherapies are required to have systemic reach to be effective as distant populations of senescent cells can affect tissue repair in other parts of the body through the SASP. Unity executives reportedly blamed an unexpectedly large placebo response; but experts say that was to be expected as saline injections have a well-known analgesic effect.⁷⁰ Despite this, given Lorecivivint’s similar lack of perceived efficacy in the short-term, one might wonder if UBX0101 may have shown positive results with an extension of the trial and if more time was given for senolytic activity to take place.
• ALK-6019 for outcomes post-arthroplasty, mild-moderate Alzheimer’s disease, severe Alzheimer’s disease and Parkinson’s disease led by Alkahest – Alkahest and its parent company Grifols have based their approach on the parabiosis theory. A theory with ancient foundations, where elderly organisms show signs of rejuvenation after being infused with the blood/plasma of their younger counterparts.⁷¹ ALK-6019 is a specific plasma-derived proteomic factor thought to bring about some of these rejuvenating effects, although it does not require blood-type matching. In the mild-moderate AD trial, it was safe and tolerable with no significant cognitive decline observed over the course of 6 months. In the PD trial, ALK-6019 was superior to placebo for multiple cognitive endpoints. Trials are still ongoing for Severe AD and post-op recovery following knee/hip arthroplasty. Alkahest is also continuing with the theme of Parabiosis through ‘The Plasma for Alzheimer SymptoM Amelioration Study’. This trial will involve intravenous administration of young donor plasma to 18 mild-moderate AD patients. Outcome measures include safety, cognitive scores, physical function and plasma markers.^{72, 73, 74, 75, 76}
• Jotrol for Friedrich’s Ataxia led by Jupiter Neurosciences – This is a resveratrol product which unlike normal resveratrol formations has good bioavailability and can cross the blood brain barrier. Resveratrol is known to improve energy regulation and mitochondrial function which has been implicated in many neurodegenerative conditions including Friedrich’s Ataxia. Jupiter Neurosciences have also made an IPO application but with phase II trials ongoing they might be overly dependent on one platform product which if positive results are not forthcoming could be very damaging. Jotrol has been granted orphan drug status by the FDA. Trials for Jotrol are also ongoing in Parkinson’s disease, mucopolysaccharidosis type I, AD and traumatic brain injury.⁷⁷ 

Growth in the longevity market

The promise demonstrated in these preclinical trials has attracted interest from longevity funds with the aim of translating these benefits to the clinic. The longevity market has been hailed by its main supporters as a future competitor to the healthcare industry. Indeed, it has shown sustained growth. From 2012-2018 total capital raised increased almost 10-fold from $1.4B to $12.2B, with a drop in 2019 to $7B. However, in subsequent years up to 2022, capital investment increased to $30.6B, indicating a growing interest in agents that influence the ageing process.^{78, 9}

Longevity research is accompanied by its own unique challenges, including research efforts that require substantial capital and long timescales to demonstrate efficacy, making them potentially riskier and costlier than other life science investments. For this reason a number of longevity-focussed VC funds have arrived with a focus on different stages of the development process.⁷⁹

Some of the most relevant global VC funds investing in longevity include:

• LongeVC - $39m fund size,
• LifeX VC - $100m fund size,
• fund - $100m fund size,
• LEAPS by Bayer - $1.5 bn fund size,
• Juvenescence - $200m fund size,
• Kizoo Technology Ventures - $330m fund size, early + late-stage.
• Apollo Health Ventures - $180m fund size,
• Maximon - $106m fund size, early
  
  

High Profile Interest

A number of high-profile individuals have announced their involvement in the longevity industry. Jeff Bezos has invested in start-ups such as Altos Labs, a biological reprogramming company, and Unity Biotechnology which has also received investment from billionaire PayPal co-founder Peter Thiel. This, while being beneficial for accelerating innovation in the longevity sector may obscure the overall purpose of senotherapy research.

While many are interested in ultimately allowing us to age more healthily and potentially stopping the onset of chronic disease there exists an undercurrent of individuals, especially the super-wealthy, who are interested in taking research further and ultimately extending lifespan substantially, as evidenced by some articles describing longevity companies as “companies that use AI and advanced algorithms to prevent death altogether.”⁸⁰

One of the faces of the industry, David Sinclair attracted interest in resveratrol’s action on Sirtuins which he became known for making statements about resveratrol such as, “(It's) as close to a miraculous molecule as you can find.... One hundred years from now, people will maybe be taking these molecules on a daily basis to prevent heart disease, stroke, and cancer.” He founded the company Sirtis, which was acquired by GlaxoSmithKline for $720 million in 2008. However, separate publications by Pfizer and Amgen scientists have challenged resveratrol’s role in sirtuin activation and whether it can impact the ageing process. For example, Pfizer scientists found that resveratrol only actually binds to SIRT1 when simultaneously bound to the fluorophore present in the assay used. Sirtris has since been shut down by GSK after clinical trials had to be halted due to adverse side effects, and because the compound's activity wasn't specific to SIRT1, at some doses it actually inhibited SIRT1.

The majority of longevity research and investment has arisen from the United States due to several factors. A high demand from an increasingly older and more unhealthy population coupled with an advanced healthcare system, many research institutions, an extensive biotech VC ecosystem and government investment. Despite Europe having a similar level of demand, longevity investment has not been as forthcoming in European markets probably due to innate conservatism and lower tolerance for risk.

Interest is growing in emerging markets in Asia, including China, Japan and Singapore, which are set to face increasing strains on health and social support systems from an ageing population. The number of journal articles published and patents filed related to anti-ageing are highest in China, with Japan and Korea not far behind. Additionally, while longevity investment was dominated by the United States from 2013-15 and 2022, Asia dominated the longevity sector in 2016-19 reflecting a growing drive for anti-ageing therapies.⁹

Source – 9, Antiageing Strategies and Remedies: A Landscape of Research Progress and Promise

 

Conclusion

In conclusion, while the field of longevity continues to face growing pains and has yet to fully shrug its association with the unregulated supplements market, biohackers and the quest for prolonging life by the ultra wealthy, it has gained much more traction as a possible viable avenue to improving health outcomes for a host of age-associated diseases. The growth in novel compounds with senotherapeutic potential entering clinical trials, along with an increased recognition amongst governments and private industry that unhealthy ageing is a major public health concern, are all boosting legitimate research in the field. While we still have a long way to go understanding the science and to results of current treatments in development, prolonging healthspan and increasing longevity, could move from concept to reality within the next few decades. If that occurs, it sets the stage for a massive change to how we approach treating a host of chronic diseases, while relegating our current ‘whack-a-mole’ healthcare model to a thing of the past. Only time will tell.

 

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⁷⁸ Pitchbook

⁷⁹ Forbes - Venture Capital Giants In The Billion-Dollar Quest For Longevity Breakthroughs (2023)

⁸⁰ Scispot - Top 20 Most Innovative Longevity Biotechs in the World