Autore: InOtherPlace

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Necrologi virtuali. What the future?

Negli ultimi anni molte agenzie funebri mettono a disposizione un cloud per i necrologi e altri servizi .

Qui prendo spunto tra uno di quelli piu sviluppati.

Infatti AnnunciFunebri.it è un servizio nato per le persone, da persone, pensato per sfruttare le potenzialità della rete a vantaggio dei rapporti umani.

Cerchiamo di coniugare semplicità e innovazione per permettere alle persone di sentirsi più vicine, ovunque si trovino e in qualsiasi momento, senza costi, senza limiti e sempre con discrezione e serietà.

Il servizio, indipendentemente dalla lunghezza del messaggio e da qualsiasi parte del mondo provenga, è sempre gratuito per gli utenti.

E al contempo per i nostri clienti del settore funebre lavoriamo sul loro brand, sulla sua unicità e sulla motivazione d’acquisto. Il nostro metodo è composto da una serie di strategie messe in atto per aumentare la visibilità dell’impresa funebre e renderla oggettivamente diversa dalla concorrenza agli occhi dei propri concittadini.



Pubblicazione e diffusione dell’ANNUNCIO FUNEBRE tramite web e social.
In modi discreti ed efficaci facciamo in modo che l’informazione della morte di una persona si “propaghi” e raggiunga quanti più interessati possibile attraverso il sito dell’impresa funebre, i social network, WhatsApp. Il tutto avviene in una cornice di discrezione senza mai urtare la sensibilità della famiglia.

Raccolta, validazione e gestione dei CORDOGLI ONLINE.
Oggi più che mai rappresentano uno strumento incredibilmente efficace per recapitare alla famiglia del defunto un messaggio di vicinanza o un ricordo legato al caro. Prima di consegnare il cordoglio il nostro staff valida i messaggi ricevuti in modo che alla famiglia non possa mai arrivare un messaggio sbagliato o fuori luogo. Una volta validati, i messaggi vengono recapitati alla famiglia tramite WhatsApp, sms e infine anche in formato cartaceo.

STREAMING DELLA CERIMONIA FUNEBRE.
Sviluppato per dare risposta alle esigenze delle prime case funerarie, questa soluzione si sta rivelando molto efficace anche in chiesa o in cimitero ed è apprezzata dalle persone che non possono essere presenti fisicamente per l’ultimo saluto alla persona cara. L’impresa funebre realizza la ripresa video della cerimonia rendendola disponibile all’interno del proprio sito.

Esistono anche altre modalità e vedremo nel futuro come la tecnologia porterà innovazione in questo settore.

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Recensione del film Resurrection.

La seconda regia di Andrew Semans, seguente Nancy, please (2012), è un thriller psicologico dai risvolti surreali, per via di un finale che parte – in maniera piacevole e sorprendente – davvero per la tangente. Il tema, compresa una conclusione apparentemente fuori logica, è simile a quello di Men (Alex Garland, 2022), ossia propone una protagonista (la strepitosa Rebecca Hall, anche coinvolta come produttrice) allergica agli uomini che la circondano. In questo caso, a differenza del film di Garland, a ben vedere data la burrascosa relazione avuta da ragazza con un pazzo (che ha il volto dell’altrettanto memorabile Tim Roth). Resurrection procede senza sosta in un percorso al limite della ragione, con il graduale sconfinamento, da parte di Margaret, verso uno stato psicologico alienante. Ma è anche un percorso di rivalsa e di riscatto, un’emancipazione, violenta e viscerale, pagata a caro prezzo, dovuta nei confronti di una donna che è anche, e soprattutto, una madre. La storia in sé non presenta motivi di particolare rilievo, se si esclude il finale imprevedibile, ma è la cura della confezione a rendere eccezionale il film. Dalla scelta di utilizzare gradazioni cromatiche fredde (azzurro, verde e grigio), da parte dell’ottimo direttore della fotografia (Wyatt Garfield), all’uso di una colonna sonora immersiva, frutto del talentuoso Jim Williams, passando per uno stile di ripresa che predilige eleganti piani sequenza e fluidi carrelli.

La telecamera segue, senza mai abbandonarla, Rebecca Hall, attrice che trasmette, a pelle, la sensazione trainante ed involutiva di un montante disagio esistenziale. La vediamo correre, agitarsi, piangere disperata, avvinta, sconvolta, spaurita, ma pur sempre determinata nel tentativo di raggiungere l’obiettivo (salvaguardare l’incolumità della figlia). Resurrection è dunque, visivamente, un gioiellino. Un amaro ritratto, work in progress e al femminile, dell’eterno conflitto tra i sessi, destinato a trovare una risoluzione che può essere solo e soltanto iperbolica. Come dimostra un finale non più accostabile al verosimile ma che ça existe, dunque è reale, anche se confinato nella mente, ormai infranta, della sfortunata protagonista.
Film TV.it

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Saremo in grado di risuscitare i morti?

La definizione di morte è sempre stata molto chiara. Ma se la morte non fosse davvero la fine? Pubblicato nella rivista «Nature», uno studio dirompente che esamina se alcune funzioni potrebbero essere ripristinate molto dopo il decesso sta rendendo indistinto il confine tra vita e morte. Lo studio suscita delle speranza mediche, ma genera anche delle questioni bioetiche. In quale momento un animale, o persino un essere umano, può essere considerato morto?

La morte è ancora reputabile come la fine?

Scienziati dell’Università di Yale hanno risuscitato l’attività cellulare in 32 cervelli provenienti da maiali che erano stati macellati a scopo alimentare 4 ore prima. Hanno collocato i cervelli all’interno di un apparato nel loro laboratorio e hanno iniziato a pompare un sostituto del sangue, appositamente progettato, attraverso gli organi. Hanno sviluppato il cosiddetto sistema BrainEx, impiegato per pompare sostanze nutritive artificiali nella rete vascolare dei cervelli.

Tuttavia, il team di ricerca sottolinea che i cervelli trattati non hanno mostrato alcuna attività elettrica che potrebbe indicare percezione, consapevolezza o coscienza. I cervelli non potevano pensare o sentire nulla, hanno rimarcato i ricercatori. «Definito in termini clinici, questo non è un cervello in vita, ma è un cervello attivo dal punto di vista cellulare», ha dichiarato Zvonimir Vrselja, coautore dello studio e ricercatore associato in neuroscienze alla Yale School of Medicine alla «Reuters».Fondamentalmente, erano ancora dei cervelli morti, quindi perché l’esperimento è importante? Esso propone una reinterpretazione di quanto si sa in merito a come muore il cervello. Finora, la convinzione era che la morte si verificasse velocemente e in modo irreversibile, venendo a mancare la fornitura di ossigeno. Citato dalla «BBC», il ricercatore principale e autore senior Nenad Sestan ha affermato: «La morte cellulare nel cervello si verifica in una finestra temporale più lunga rispetto a quanto si riteneva in precedenza. Ciò che stiamo mostrando è che il processo della morte cellulare è graduale e progressivo e che alcuni di quei processi possono essere posticipati, preservati o persino invertiti». Ha aggiunto: «Non sappiamo ancora se saremo in grado di ripristinare una normale funzione cerebrale».

Supposizioni impegnative riguardo al danno cerebrale umano

In un commento di accompagnamento su «Nature», i bioetici Stuart Youngner e Insoo Hyun della Case Western Reserve School of Medicine a Cleveland rilevano che se questo lavoro dovesse portare a migliori tecniche per resuscitare il cervello delle persone, esso potrebbe complicare ulteriormente le decisioni relative a quando espiantare gli organi per il trapianto. Sono preoccupati di ciò che un sistema di supporto vitale per il cervello potrebbe significare per coloro che sono in attesa del trapianto di organi.

I due bioetici incoraggiano un sano dibattito. «A nostro modo di vedere, lo studio BrainEx, e il lavoro successivo che sicuramente verrà ispirato da esso, evidenziano la necessità di una discussione più aperta. Un dibattito che coinvolge chiunque, dai neuroscienziati e dai responsabili delle politiche ai pazienti e al personale medico, potrebbe aiutare a chiarire quali criteri rendono un soggetto idoneo alla donazione degli organi rispetto che non alla rianimazione. Tali discussioni possono anche approfondire in che modo garantire che la donazione di organi possa essere integrata nella cura del fine vita suscitando un livello minimo di controversie».

Concludono: «I ricercatori sono ancora ben lontani dall’essere in grado di ripristinare strutture e funzioni nel cervello di persone che sarebbero oggi dichiarate morte. Ma, a nostro modo di vedere, non è troppo presto per prendere in considerazione come questo tipo di ricerca potrebbe interessare la crescente popolazione di pazienti gravemente malati che sono in attesa di reni, fegati, polmoni o cuori».

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Le cere di Cronenberg

Se avete un pò di tempo non posso che invitarvi a visitare la mostra presso la Fondazione Prada di David Cronenberg : Cere anatomiche.

La mostra riunisce tredici ceroplastiche del XVIII secolo provenienti dalla prestigiosa raccolta del museo fiorentino, e una serie di settantadue copie espositive di disegni anatomici raccolti in nove vetrine. In particolare, sono presentate quattro figure femminili distese, tra le quali una delle opere più importanti della collezione del museo La Specola, la cosiddetta Venere, un raro modello con parti scomponibili conosciuto per la sua bellezza.
Un inedito cortometraggio, realizzato da David Cronenberg negli spazi della Specola, introduce queste quattro cere in una dimensione alternativa, esplorando temi come la fascinazione per il corpo umano e le sue possibili mutazioni e contaminazioni. Il film di Cronenberg rivela la dimensione vitale e sorprendente delle ceroplastiche con l’obiettivo di generare una pluralità di nuove risposte emotive, suggestioni intellettuali e intense reazioni.

Come spiega David Cronenberg: “Le figure di cera della Specola furono create prima di tutto come strumento didattico, in grado di svelare i misteri del corpo umano a chi non poteva accedere alle rare lezioni anatomiche con veri cadaveri tenute nelle università e negli ospedali. Nel loro tentativo di creare delle figure intere parzialmente dissezionate, il cui linguaggio corporeo ed espressione facciale non mostrassero sofferenza o agonia e non suggerissero l’idea di torture, punizioni o interventi chirurgici, gli scultori finirono col produrre personaggi viventi apparentemente travolti dall’estasi. È stata questa sorprendente scelta stilistica che ha catturato la mia immaginazione: e se fosse stata la dissezione stessa a indurre quella tensione, quel rapimento quasi religioso?”

Il progetto si configura come un duplice intervento: la narrazione scientifica e quella artistica prendono forma in due allestimenti indipendenti realizzati dall’agenzia creativa Random Studio. Al primo piano del Podium le cere del museo La Specola sono esposte seguendo un rigoroso approccio museale. Al piano terra le stesse opere accedono all’immaginario del regista diventando le protagoniste di un enigmatico processo di metamorfosi.

Tutto questo potete visitarlo dal 24 marzo al 17 luglio 2023

Fondazione PRADA

LARGO ISARCO, 2
20139 MILANO

Warning:

Flash light.

Nudity, sensitive contenents.

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Elaborazione del lutto.

Nell’avvicinarsi alla fine della vita di un proprio caro, bisogna coniugare la speranza con il realismo. La morte è un evento estremamente doloroso; ha bisogno di tempo per essere accettata perché è normale che le emozioni negative siano molto forti.

Il tempo per elaborare la morte è variabile da persona a persona; quando ci si confronta con una malattia grave, è normale mettere in atto dei meccanismi mentali per iniziare ad accettare un lutto. Ci sono delle emozioni che si alternano e che possono ripresentarsi nel tempo, con diversa intensità, e senza un preciso ordine.



Negazione o rifiuto: la morte, prima o dopo che questa sia avvenuta, viene rifiutata, non accettata. La mente, in questo modo, cerca di proteggersi da un’eccessiva ansia e di prendersi il tempo necessario ad organizzarsi, sia praticamente che emotivamente.

Rabbia: si possono manifestare emozioni forti quali rabbia e paura, che esplodono in tutte le direzioni, investendo i familiari, il personale ospedaliero, Dio.

Contrattazione o patteggiamento: quando si inizia a riconoscere ciò che sta capitando o che è già capitato; costituisce il primo vero contatto con il proprio dolore interiore.

Depressione: arriva spesso nel momento in cui si inizia a prendere consapevolezza della perdita di una persona cara. La depressione preparatoria anticipa il timore della morte di una persona cara, come se la mente si stesse preparando. La depressione reattiva nasce quando ci si accorge che molti aspetti della propria vita stanno cambiando e determina un forte senso di impotenza.

Accettazione: ad un certo punto, è normale che anche le emozioni seguano la razionalità. La consapevolezza di ciò che accade può non proteggere completamente dalla rabbia e dalla depressione, ma ne limita l’intensità.



E’ normale avere emozioni molto forti davanti alla morte di una persona cara. La condivisione di queste emozioni difficili con le persone a cui vuoi bene ti può aiutare a reagire positivamente, facendoti sentire meno solo e rendendo questo momento di dolore più accettabile.

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La vita è un film; la morte è una fotografia. – Susan Sontag

Il fotogiornalismo, in particolare, è intrinsecamente legato al soggetto, poiché, sin dal suo inizio, è stato saldamente fondato sulla guerra, con Roger Fenton, Valle dell’ombra della morte, (uno degli oltre trecento catturati durante la guerra di Crimea) la prima rappresentazione iconica di questo tipo. Come tutte le sue immagini, la morte umana non è raffigurata, ma le centinaia di palle di cannone che tappezzano la strada, simboleggiano lo spargimento di sangue che ha avuto luogo lì.

Gli ultimi anni hanno visto immagini sorprendenti che rappresentano la morte di un tipo diverso: quella del nostro pianeta. Poche regioni esemplificano questa distruzione ecologica in modo più vivido della foresta pluviale amazzonica; il più grande del mondo, comprende oltre la metà della restante foresta pluviale della terra, ma è in rapido declino, accelerato in modo drammatico dai recenti incendi che hanno avvolto gran parte della regione.

Fotografo spagnolo Sebastián Liste ha documentato gran parte della devastazione, inclusa questa straordinaria immagine di una chiesa travolta dalle fiamme. Intriso di simbolismo apocalittico: il bagliore infernale delle fiamme che penetrano nell’oscurità; la croce solitaria; agisce sia come un cupo testamento degli incendi, sia come potente metafora della distruzione del nostro pianeta nel suo complesso.

Come abbiamo visto, il rapporto della fotografia con la morte è sia lungo che storico; un rapporto che ha prodotto alcune delle immagini più importanti della storia e che senza dubbio continuerà. L’incombente ineludibilità della morte lo rende un argomento che risuona profondamente con tutti noi.

https://independent-photo.com/it/

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Come le opere sopravvivono al tempo.

L’espressione artistica osa affrontarne ogni tematica superando le reticenze che nella cultura contemporanea hanno reso complesso il rapporto tra vita e morte. Non sappiamo se per l’audacia tipica dell’arte o per la “compliance”, ma l’arte sopravvive alla morte stessa. L’arte sopravvive all’artista che la genera e dura a lungo nel tempo. Se pensiamo alla vita media di un’opera d’arte, anche la più fragile, comprendiamo essere di gran lunga superiore alla vita degli esseri umani e già questo dice molto del rapporto tra arte, vita e morte.

L’aspetto dell’arte che coinvolge la disciplina della conservazione e restauro è l’aspetto della conservazione materiale delle opere d’arte. L’obiettivo di conservare l’opera d’arte nel tempo nel suo aspetto materiale. In una dimensione vitale.
Partendo dal presupposto che l’arte si esprime attraverso l’elaborazione sapiente della materia, per lo stesso assioma, letto in maniera inversa, la materia che ci attornia attraverso mani sapienti e menti creative diviene arte. Questa premessa è doverosa perché l’arte, soprattutto quella antica, è spesso costituita nella sua essenza fisica da materie semplici, materie prime tratte dalla natura. In fondo, se si escludono i materiali di sintesi, anche il mondo che ci circonda è costruito a partire da materie prime naturali piuttosto semplici, reperibili in natura. Considerazioni che possono valere per tutta l’arte dai secoli più remoti sino a gran parte dell’arte recente, tranne che per certi filoni dell’arte contemporanea i cui supporti per le espressioni artistiche meriterebbero un discorso a parte, poiché possono essere videoregistrazioni, audio o supporti immateriali. Tuttavia, pur nella specificità del mezzo espressivo, anche in quel caso potremmo individuare lo stesso sapiente presupposto di gestione dello strumento virtuale anziché della materia.
In definitiva i manufatti artistici hanno una vita che, seppur più lunga di quella umana, ha comunque un tempo più o meno prevedibile. La disciplina del restauro ha come obiettivo principale la cura e la conservazione dei manufatti nella loro essenza materiale, ha la finalità di allungare la vita della materia che compone le opere d’arte.
Il concetto di cura e conservazione delle opere d’arte è piuttosto complesso e coinvolge discipline umanistiche e scientifiche allo stesso tempo, l’utilizzo di materiali della tradizione e sperimentazione degli ultimi ritrovati delle innovazioni tecnico scientifiche.
Per semplificare potremmo individuare una duplice componente dell’azione conservativa di un’opera: una pertinente alla sfera umanistica, quella attinente all’ambito concettuale che definisce l’obiettivo, il fine e le caratteristiche estetiche dell’intervento conservativo. E un’altra, la seconda, quella scientifica, che stabilisce il percorso e le modalità conservative dell’intervento partendo dalla specifica e peculiare materia che compone l’opera. Per affrontare questo secondo aspetto dovremmo entrare in dettagli che attengono alla sfera della chimica e della fisica, della compatibilità tra i materiali antichi e quelli contemporanei ed esplicare il concetto basilare della reversibilità dell’intervento di restauro.
In sostanza il restauro è una continua lotta ideale tra bene e male; si tratta di una disciplina piuttosto recente, una materia dove nulla è chiaro, palese e scontato, una disciplina che richiede metodo, attenzione e studio. Flessibilità nel modificare l’atteggiamento e il percorso a seconda delle esigenze specifiche che il singolo caso potrà porre.
Per fare un esempio, conservare un manufatto deve consentire la vita dello stesso e dovrà perciò evitare che gli interventi divengano “mummificazioni”. Premesso che il restauro, come ogni attività e disciplina umana, è soggetto alle mode e a variazioni di atteggiamento conservativo.

attribuendo.com

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New horizons in life extension, healthspan extension and exceptional longevity.

Age and Ageing
Oxford University Press


Abstract
Many common chronic diseases and syndromes are ageing-related. This raises the prospect that therapeutic agents that target the biological changes of ageing will prevent or delay multiple diseases with a single therapy. Gerotherapeutic drugs are those that target pathways involved in ageing, with the aims of reducing the burden of ageing-related diseases and increasing lifespan and healthspan. The approach to discovering gerotherapeutic drugs is similar to that used to discover drugs for diseases. This includes screening for novel compounds that act on receptors or pathways that influence ageing or repurposing of drugs currently available for other indications. A novel approach involves studying populations with exceptional longevity, in order to identify genes variants linked with longer lifespan and could be targeted by drugs. Metformin, rapamycin and precursors of nicotinamide adenine dinucleotide are amongst the frontrunners of gerotherapeutics that are moving into human clinical trials to evaluate their effects on ageing. There are also increasing numbers of potential gerotherapeutic drugs in the pipeline or being studied in animal models. A key hurdle is designing clinical trials that are both feasible and can provide sufficient clinical evidence to support licencing and marketing of gerotherapeutic drugs.


Gerotherapeutic drugs target ageing pathways to prevent ageing-related diseases and increase lifespan.
Rapamycin, metformin and precursors of NAD are amongst many gerotherapeutic drugs entering the clinical trial phase of drug development.
Licencing of gerotherapeutic drugs will depend on clinical trials that are both feasible and can provide evidence of a primary impact on ageing biology.
Introduction
The majority of people would like to live to the age of 120 years or more if their health remained good and nearly one half would like an unlimited lifespan . About one-third of people would be prepared to take life extension or anti-ageing therapies now.The possibility that a pill might prevent ageing and increase lifespan is tantalising for most people. As a result, anti-ageing and life extension therapies are often the focus for media hype despite the absence of definitive human data.

In this review, the term ‘gerotherapeutics’ is used to refer to drugs that target ageing biology, and that have been developed using similar approaches to those used to develop drugs for diseases. A major scientific endeavour is underway to find biological switches that can manipulate ageing. This research aims to discover new gerotherapeutic drugs that both reduce the burden of ageing-related diseases, and extend lifespan . There are many ageing-related diseases where the incidence increases exponentially throughout old age, including Alzheimer’s disease, some cancers, ischaemic heart disease, ischemic stroke and chronic obstructive pulmonary disease [6]. The biological changes of ageing are a major risk factor these diseases .The hope is that gerotherapeutic drugs might reduce the impact of these ageing-related diseases with a single therapy.

Over the last two decades there has been a marked increase in the number of interventions reported to increase lifespan, and delay ageing and disease, in laboratory animals. However, the development of gerotherapeutic drugs is still in its infancy, and no gerotherapeutic drug has yet been shown to increase human lifespan or been licenced for an indication related to ageing.

‘Anti-ageing’ is a term mostly used to promote products that are not regulated or licenced. There are many drugs, supplements and other treatments that are marketed as anti-ageing and can be accessed direct-to-consumer from pharmacies or online. This global anti-ageing drugs market is estimated to be USD82 billion in 2020 [8]. None of these treatments can support their anti-ageing claims with high quality clinical trials equivalent to those that are required for the registration of drugs for the treatment of individual diseases.

There is very little information about how many people are taking anti-ageing therapies and gerotherapeutic drugs or what they are taking. It is likely that most doctors, including geriatricians, will have some or many patients using these treatments without supervision, so will need to have some knowledge about them.

This is the first review on this topic in Age and Ageing. It focuses on gerotherapeutics that have an established basic scientific foundation and/or where there is the possibility of widespread use in the community. It also provides a summary of how these drugs are being discovered, using traditional drug discovery approaches, repurposing, or by investigating populations with exceptional .


The overall process of drug discovery of gerotherapeutics has so far been similar to that used to discover drugs for the treatment of individual diseases. The foundation for discovering gerotherapeutic drugs is a detailed understanding of the biology of ageing. This knowledge is used to identify ageing pathways and proteins that can be manipulated by drugs [9]. The aim is to find novel compounds that can be protected by patents and then generate profits to offset the substantial costs involved in bringing any new drug to the market.

The biological processes of ageing that are potential targets for gerotherapeutics have been classified into nine groups called the Hallmarks of Ageing. These are currently considered to be the fundamental processes of ageing, or at least reflect the current major domains of research in ageing biology. The Hallmarks are interconnected and integrated. This means that a drug that acts on just one Hallmark can potentially influence the other Hallmarks, and hence the entire ageing process. The Hallmarks of Ageing are a useful platform for grouping gerotherapeutics on the basis of their major mechanisms [9].

Repurposing provides another pathway for drug development. Here, drugs that are already registered for unrelated diseases and have established safety, are tested for additional indications [9]. In the case of gerotherapeutics, an innovative process involving detailed analysis of clinical and preclinical effects on lifespan, healthspan and ageing biology found nine drugs that could potentially be repurposed for their ageing or ‘gerotherapeutic’ effects. These were: sodium-glucose cotransporter-2 (SGLT2) inhibitors, metformin, acarbose, rapamycin/rapalogs, methylene blue, ACEi/ARB, dasatinib (and quercetin), aspirin and N-acetyl cysteine . Metformin, rapamycin and the combination of dasatinib and quercetin have already been extensively studied for their effects on ageing.

As with all drugs, the pivotal step for any gerotherapeutic will be undertaking high quality clinical trials that prove clinical efficacy and acceptable safety, and comply with international regulatory guidelines. The detailed format for clinical trials of gerotherapeutics has not yet been formalised. The primary outcomes should ideally include lifespan, healthspan and ageing-related diseases. In the past the main aim of life extension therapy has been, by definition, to increase life span.

More recently, the value of increasing healthspan, which is the duration of healthy life before the onset of disease or disability, has been emphasised. Recent studies of gerotherapeutics in laboratory animals have been more like to report increases in healthspan measured by latelife health, than increases in lifespan.

Although ageing-related diseases are poorly defined, it is believed that therapies targeting ageing might delay or prevent multiple ageing-related diseases. This will be preferable to the current medical approach of treating each disease individually, with the associated risks of polypharmacy and over-medicalisation . However, due to funding and duration constraints, human clinical trials of gerotherapeutics with the primary outcomes of lifespan and healthspan are unlikely to be feasible. Instead there has been an attempt to develop biomarkers of ageing that reflect ageing biology and can act as surrogate markers for these outcomes in clinical research.Metformin
It may be surprising to many clinicians that metformin, the common anti-diabetic drug that was first available in 1957, is also widely lauded as for its potential effects on ageing.

It was initially proposed that metformin might be a CR-mimetic, a drug that replicates the ageing benefits of caloric restriction without any need to alter diet. Rather than being simply a CR-mimetic, metformin has now been found to have effects on all the Hallmarks of Ageing. Amongst its actions, metformin interacts with mitochondrial complex 1 and activates the AMP-activated protein kinase (AMPK) pathway. This leads to increased insulin sensitivity and decreased mTOR signalling, oxidative stress, genetic instability and inflammation.

As reviewed elsewhere human clinical trials have shown the metformin has many effects apart from managing hyperglycaemia in type 2 diabetes. These include two pivotal clinical trials related to the use of metformin in diabetes: the Diabetes Prevention (DPP) study, which found that metformin prevented type 2 diabetes in non-diabetics; and the UK Prospective Diabetes Study (UKPDS), which found that it reduced cardiovascular outcomes and diabetes related deaths in people with type 2 diabetes. There are many (>250) other studies and systematic reviews concluding that metformin can also reduce mortality, cancers, cardiovascular events, dementia and cognitive impairment.

This combination of human clinical studies and preclinical data on the ageing effects of metformin, together with its established safety record led to metformin becoming one of the first drugs to be considered for human ageing trials. Led by Nir Barzilai, ‘Targeting Ageing with Metformin’ (TAME) is a 6-year, double blind, randomised, placebo-controlled diet evaluating metformin in 3,000 non-diabetic participants aged 65–80 years of age. Outcomes include age-related diseases and biomarkers of ageing. Although there are already convincing studies of metformin and cardiovascular disease, cancer and cognition [19], the purpose of TAME is to use metformin as a tool that will tie those outcomes in a cluster that will give a green light to study ageing outcomes for other gerotherapeutics in the pipeline.

Rapamycin
Rapamycin, in high doses is an immunosuppressant used in organ transplantation. However, its main physiological main action is to inhibit its eponymous receptor, Mechanistic Target of Rapamycin (MTOR). The MTOR pathway is a nutrient sensing pathway that responds to increased levels of amino acids by increasing protein synthesis via activation of transcription. Inhibition of MTOR by rapamycin leads to a reduction protein synthesis. Rapamycin, like metformin was initially thought to be a CR-mimetic [20] but since has been shown to have effects that are distinct from caloric restriction [21] and influences other Hallmarks of Ageing such as autophagy and stem cells.

Rapamycin increases the lifespan of mice, even when commenced in mid-life and late life. Studies undertaken at the National Institute of Ageing Interventions Testing Program showed that lifespan of mice commenced on rapamycin at the old age of 20 months increased by 9% in females and 14% in males [22], and by 18% in females and 10% in males when started at 9 months [23]. This was associated with lower rates of diseases and age-related pathology.

A small clinical trial in healthy older people aged 70–95 years found that rapamycin was safe over 8 weeks .

A trial of two rapamycin-like drugs (‘rapalogs’) in 264 participants 65 years and older found that they were associated with a reduction in infections, improved influenza vaccination responses and antiviral immunity . In an novel twist, the effect of rapamycin on ageing is also being trialled in companion dogs.

NAD precursors.


NAD is a ubiquitous metabolite involved in many fundamental cellular pathways including those maintaining redox status, DNA repair and bioenergetics. Ageing is associated with reduced levels of NAD in many tissues, and depletion of NAD influence many ageing hallmarks.

Because NAD is a naturally occurring metabolite, there has been considerable interest in establishing the effects of NAD supplementation on ageing. Most studies have used NAD precursors (nicotinamide mononucleotide, NMN; nicotinamide riboside NR and nicotinamide NAM) because of their greater intracellular bioavailability. In vitro and animal experiments have shown that NAD supplementation can prevent or reverse a wide range of age-related pathologies and Hallmarks [30, 31].

Lifespan studies have been undertaken in mice. One study reported an increase in lifespan of 5% when old mice were administered NR in food for 6 weeks , whereas another reported that 62 weeks of supplementation with NAM commenced in midlife did not increase lifespan. Recently the Interventions Testing Program confirmed that NR commenced in midlife or old age had no effect on lifespan.

There are >30 human clinical trials of NR and NMN registered in clinicaltrials.org [28]. To date, published studies of NR have mostly evaluated its bioavailability [33], whereas there have been some recent studies of NMN that have evaluated clinical outcomes in older adults. A 12-week period of treatment with NMN reduced drowsiness and improved leg function in older people [34]. A randomised clinical trial in 25 obese postmenopausal women found that 10 weeks of NMN compared to placebo was associated with improved insulin sensitivity in muscle but not liver or adipose tissue [35]. It should be noted that these are all very small studies where multiple outcomes were evaluated.

Age and Ageing
Oxford University Press
New horizons in life extension, healthspan extension and exceptional longevity
David G Le Couteur and Nir Barzilai

Additional article information

Abstract
Many common chronic diseases and syndromes are ageing-related. This raises the prospect that therapeutic agents that target the biological changes of ageing will prevent or delay multiple diseases with a single therapy. Gerotherapeutic drugs are those that target pathways involved in ageing, with the aims of reducing the burden of ageing-related diseases and increasing lifespan and healthspan. The approach to discovering gerotherapeutic drugs is similar to that used to discover drugs for diseases. This includes screening for novel compounds that act on receptors or pathways that influence ageing or repurposing of drugs currently available for other indications. A novel approach involves studying populations with exceptional longevity, in order to identify genes variants linked with longer lifespan and could be targeted by drugs. Metformin, rapamycin and precursors of nicotinamide adenine dinucleotide are amongst the frontrunners of gerotherapeutics that are moving into human clinical trials to evaluate their effects on ageing. There are also increasing numbers of potential gerotherapeutic drugs in the pipeline or being studied in animal models. A key hurdle is designing clinical trials that are both feasible and can provide sufficient clinical evidence to support licencing and marketing of gerotherapeutic drugs.


Key Points
Gerotherapeutic drugs target ageing pathways to prevent ageing-related diseases and increase lifespan.
Rapamycin, metformin and precursors of NAD are amongst many gerotherapeutic drugs entering the clinical trial phase of drug .

In this review, the term ‘gerotherapeutics’ is used to refer to drugs that target ageing biology, and that have been developed using similar approaches to those used to develop drugs for diseases. A major scientific endeavour is underway to find biological switches that can manipulate ageing. This research aims to discover new gerotherapeutic drugs that both reduce the burden of ageing-related diseases, and extend lifespan [4, 5]. There are many ageing-related diseases where the incidence increases exponentially throughout old age, including Alzheimer’s disease, some cancers, ischaemic heart disease, ischemic stroke and chronic obstructive pulmonary disease [6]. The biological changes of ageing are a major risk factor these diseases [4, 5, 7]. The hope is that gerotherapeutic drugs might reduce the impact of these ageing-related diseases with a single therapy.

Over the last two decades there has been a marked increase in the number of interventions reported to increase lifespan, and delay ageing and disease, in laboratory animals. However, the development of gerotherapeutic drugs is still in its infancy, and no gerotherapeutic drug has yet been shown to increase human lifespan or been licenced for an indication related to ageing.

‘Anti-ageing’ is a term mostly used to promote products that are not regulated or licenced. There are many drugs, supplements and other treatments that are marketed as anti-ageing and can be accessed direct-to-consumer from pharmacies or online. This global anti-ageing drugs market is estimated to be USD82 billion in 2020 [8]. None of these treatments can support their anti-ageing claims with high quality clinical trials equivalent to those that are required for the registration of drugs for the treatment of individual diseases.

There is very little information about how many people are taking anti-ageing therapies and gerotherapeutic drugs or what they are taking. It is likely that most doctors, including geriatricians, will have some or many patients using these treatments without supervision, so will need to have some knowledge about them.

This is the first review on this topic in Age and Ageing. It focuses on gerotherapeutics that have an established basic scientific foundation and/or where there is the possibility of widespread use in the community. It also provides a summary of how these drugs are being discovered, using traditional drug discovery approaches, repurposing, or by investigating populations with exceptional longevity.

Drug discovery and drug development in ageing
The overall process of drug discovery of gerotherapeutics has so far been similar to that used to discover drugs for the treatment of individual diseases. The foundation for discovering gerotherapeutic drugs is a detailed understanding of the biology of ageing. This knowledge is used to identify ageing pathways and proteins that can be manipulated by drugs [9]. The aim is to find novel compounds that can be protected by patents and then generate profits to offset the substantial costs involved in bringing any new drug to the market.

The biological processes of ageing that are potential targets for gerotherapeutics have been classified into nine groups called the Hallmarks of Ageing. These are currently considered to be the fundamental processes of ageing, or at least reflect the current major domains of research in ageing biology. The Hallmarks are interconnected and integrated. This means that a drug that acts on just one Hallmark can potentially influence the other Hallmarks, and hence the entire ageing process. The Hallmarks of Ageing are a useful platform for grouping gerotherapeutics on the basis of their major mechanisms [9].

Repurposing provides another pathway for drug development. Here, drugs that are already registered for unrelated diseases and have established safety, are tested for additional indications [9]. In the case of gerotherapeutics, an innovative process involving detailed analysis of clinical and preclinical effects on lifespan, healthspan and ageing biology found nine drugs that could potentially be repurposed for their ageing or ‘gerotherapeutic’ effects. These were: sodium-glucose cotransporter-2 (SGLT2) inhibitors, metformin, acarbose, rapamycin/rapalogs, methylene blue, ACEi/ARB, dasatinib (and quercetin), aspirin and N-acetyl cysteine [10]. Metformin, rapamycin and the combination of dasatinib and quercetin have already been extensively studied for their effects on ageing.

More recently, the value of increasing healthspan, which is the duration of healthy life before the onset of disease or disability, has been emphasised. Recent studies of gerotherapeutics in laboratory animals have been more like to report increases in healthspan measured by latelife health, than increases in lifespan.

Although ageing-related diseases are poorly defined, it is believed that therapies targeting ageing might delay or prevent multiple ageing-related diseases. This will be preferable to the current medical approach of treating each disease individually, with the associated risks of polypharmacy and over-medicalisation [5]. However, due to funding and duration constraints, human clinical trials of gerotherapeutics with the primary outcomes of lifespan and healthspan are unlikely to be feasible. Instead there has been an attempt to develop biomarkers of ageing that reflect ageing biology and can act as surrogate markers for these outcomes in clinical research.

Nutrient sensing pathways
Many strains and species of animals, when given significantly less food than they would eat if food was freely available, have longer lifespans, reduced cancers and delayed onset of ageing changes. This is called caloric restriction. Conversely, overeating and obesity can be potentially considered to be accelerated ageing and is associated with accumulation of all the Hallmarks of Ageing.



Metformin
It may be surprising to many clinicians that metformin, the common anti-diabetic drug that was first available in 1957, is also widely lauded as for its potential effects on ageing.

It was initially proposed that metformin might be a CR-mimetic, a drug that replicates the ageing benefits of caloric restriction without any need to alter diet. Rather than being simply a CR-mimetic, metformin has now been found to have effects on all the Hallmarks of Ageing. Amongst its actions, metformin interacts with mitochondrial complex 1 and activates the AMP-activated protein kinase (AMPK) pathway. This leads to increased insulin sensitivity and decreased mTOR signalling, oxidative stress, genetic instability and inflammation.

As reviewed elsewhere human clinical trials have shown the metformin has many effects apart from managing hyperglycaemia in type 2 diabetes. These include two pivotal clinical trials related to the use of metformin in diabetes: the Diabetes Prevention (DPP) study, which found that metformin prevented type 2 diabetes in non-diabetics; and the UK Prospective Diabetes Study (UKPDS), which found that it reduced cardiovascular outcomes and diabetes related deaths in people with type 2 diabetes. There are many (>250) other studies and systematic reviews concluding that metformin can also reduce mortality, cancers, cardiovascular events, dementia and cognitive impairment.

This combination of human clinical studies and preclinical data on the ageing effects of metformin, together with its established safety record led to metformin becoming one of the first drugs to be considered for human ageing trials. Led by Nir Barzilai, ‘Targeting Ageing with Metformin’ (TAME) is a 6-year, double blind, randomised, placebo-controlled diet evaluating metformin in 3,000 non-diabetic participants aged 65–80 years of age. Outcomes include age-related diseases and biomarkers of ageing. Although there are already convincing studies of metformin and cardiovascular disease, cancer and cognition [19], the purpose of TAME is to use metformin as a tool that will tie those outcomes in a cluster that will give a green light to study ageing outcomes for other gerotherapeutics in the pipeline.

Rapamycin
Rapamycin, in high doses is an immunosuppressant used in organ transplantation. However, its main physiological main action is to inhibit its eponymous receptor, Mechanistic Target of Rapamycin (MTOR). The MTOR pathway is a nutrient sensing pathway that responds to increased levels of amino acids by increasing protein synthesis via activation of transcription. Inhibition of MTOR by rapamycin leads to a reduction protein synthesis. Rapamycin, like metformin was initially thought to be a CR-mimetic [20] but since has been shown to have effects that are distinct from caloric restriction [21] and influences other Hallmarks of Ageing such as autophagy and stem cells.

Rapamycin increases the lifespan of mice, even when commenced in mid-life and late life. Studies undertaken at the National Institute of Ageing Interventions Testing Program showed that lifespan of mice commenced on rapamycin at the old age of 20 months increased by 9% in females and 14% in males [22], and by 18% in females and 10% in males when started at 9 months [23]. This was associated with lower rates of diseases and age-related pathology.

NAD precursors
NAD is a ubiquitous metabolite involved in many fundamental cellular pathways including those maintaining redox status, DNA repair and bioenergetics. Ageing is associated with reduced levels of NAD in many tissues, and depletion of NAD influence many ageing hallmarks.

Because NAD is a naturally occurring metabolite, there has been considerable interest in establishing the effects of NAD supplementation on ageing. Most studies have used NAD precursors (nicotinamide mononucleotide, NMN; nicotinamide riboside NR and nicotinamide NAM) because of their greater intracellular bioavailability. In vitro and animal experiments have shown that NAD supplementation can prevent or reverse a wide range of age-related pathologies and Hallmarks.

Lifespan studies have been undertaken in mice. One study reported an increase in lifespan of 5% when old mice were administered NR in food for 6 weeks [30], whereas another reported that 62 weeks of supplementation with NAM commenced in midlife did not increase lifespan . Recently the Interventions Testing Program confirmed that NR commenced in midlife or old age had no effect on lifespan.

There are >30 human clinical trials of NR and NMN registered in clinicaltrials.org [28]. To date, published studies of NR have mostly evaluated its bioavailability [33], whereas there have been some recent studies of NMN that have evaluated clinical outcomes in older adults. A 12-week period of treatment with NMN reduced drowsiness and improved leg function in older people [34]. A randomised clinical trial in 25 obese postmenopausal women found that 10 weeks of NMN compared to placebo was associated with improved insulin sensitivity in muscle but not liver or adipose tissue [35]. It should be noted that these are all very small studies where multiple outcomes were evaluated.

Other gerotherapeutics in the pipeline
There are many biotech companies that are developing drugs that have been designed to act on ageing pathways [36]. However the majority of these have nominated a specific age-related disease, rather than ageing, as the therapeutic target. This likely reflects the current regulatory environment where ageing has not yet been established to be a licensable indication, and the higher costs and lower feasibility of undertaking clinical trials where ageing is the outcome, compared with those where an age-related disease or syndrome is the outcome [9].

One group of drugs receiving considerable attention currently, are the senolytics. Senescence cells are cells that have stopped dividing. These cells often produce an inflammatory cocktail called the ‘senescence associated secretory phenotype’ (SASP) that contributes to age-related inflammation . Senolytic drugs target and destroy senescent cells. Front runners amongst the senolytics are the combination of dasatinib, which is a tyrosine kinase inhibitor used in leukaemia, with quercetin which is a naturally occurring flavonoid antioxidant [38]. Two early phase clinical small trials have reported that treatment with dasatinib and quercetin is associated with clinical improvement in pulmonary fibrosis and decreased numbers of senescent cells and SASP levels.

In the recent past, resveratrol and the Sirtuin Activating Compounds (STACs) had a very high profile in the media. Studies in laboratory animal models had identified the sirtuins, in particular SIRT1, as important regulators of ageing. Initial studies were undertaken with resveratrol, a naturally occurring SIRT1 agonist, and later a range of other compounds (STACs) that increase SIRT1 activity. Resveratrol and STACs delayed ageing and increased lifespan in some animal models. After many trials in humans did not find major effectiveness of these drugs for a range of indications, further clinical development was shelved.

A natural product similar to resveratrol, called pterostilbene has been combined with NR in a fixed dose combination oral capsule. It is claimed that this combination of drugs will both replenish NAD and increase the activity of sirtuins, providing a multipronged approach to delay ageing. Human trial data proving efficacy in any aspect of ageing has not yet been published. However a small placebo controlled trial in 32 participants with amyotrophic lateral sclerosis reported clinical improvement after 4 months of treatment with pterostilbene and NR [43]. Social media marketing of this drug combination emphasises the basic ageing science supporting these claims, and endorsement by high profile scientists. The product has been available online and likely has substantial international market penetration.

There are many other gerotherapeutics in the drug development pipeline and many more available direct-to-consumer [8, 36]. Only a small fraction of these are discussed in this review. The basic science and animal lifespan data underlying gerotherapeutics often can be exciting and compelling. However, as in all other areas of medicine, the use of drug therapies in people must be supported by clinical trial evidence proving that there is both efficacy and acceptable safety. This is even more important for treatments that are claimed to delay ageing, where healthy people without disease may want to take these drugs, potentially for many decades.



Conclusions
The discovery of gerotherapeutics has been facilitated by the increased understanding of the biological mechanisms for ageing. This has shown that there are a wide range of cellular pathways that can manipulated by drugs to delay ageing and ageing-related diseases. Such drugs have often led to remarkable outcomes in laboratory animal models. However, there has not been any convincing evidence from high quality clinical trials in humans that any gerotherapeutic drug should be made available to delay ageing, but for the example of metformin. However, in order to define the therapy as gerotherapeutics it has to be tested for effects of a cluster of seemingly unrelated diseases whose major risk is ageing. Even so, ongoing research is motivated by the enormous potential benefits of gerotherapeutics, especially the possibility of delaying multiple ageing-related diseases with a single therapy.

Contributor Information
David G Le Couteur, Department of Geriatric Medicine, Concord Hospital, Sydney, Australia.

Nir Barzilai, Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY, USA.

Per informazioni più complete potete visitare il sito:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9356533/